Department of Genetics, Stanford UniversitySponsor: Karla Kirkegaard
Determining how diverse RNA viruses manipulate the autophagy pathway
Viruses make excellent tools for studying host pathways because they have evolved ways to subvert or co-opt those pathways. I’m interested in the autophagy pathway- a highly conserved means for the cell to recycle cellular material during times of stress by promoting vesicle formation and subsequent degradation of cytoplasmic contents. Autophagy is a fascinating and broad-reaching area of research where there is still little mechanistic knowledge, but appears to be involved in many different diseases including cancer, neurodegenerative diseases, and infectious diseases.
I’m particularly interested in how viruses co-opt this pathway to promote their own replication and spread. To address the mechanisms by which viruses induce and interact with the autophagy pathway, I am using poliovirus infection in HeLa cells that have several key autophagy genes knocked out by Crispr-Cas9. This will allow me to explore how the virus interfaces with the distinct complexes of the autophagy pathway and how the virus utilizes these for replication. Using viruses to study this underlying cellular process may help uncover potential drug targets for other diseases where autophagy is implicated.
Department of Molecular and Cell Biology, University of California, Berkeley, CaliforniaRead more
Department of Molecular and Cell Biology, University of California, Berkeley, CaliforniaSponsor: Dr. John Kuriyan
Substrate docking and ubiquitylation in the E3 ligase Cbl , with John Kuriyan
Post-translational modifications regulate key interactions in signaling pathways. In protein tyrosine kinase (PTK) signaling, for example, crosstalk between phosphorylation and ubiquitylation signals is critical to proper cellular function. A phosphorylation cascade is triggered upon PTK activation; in turn, the RING-type E3 ubiquitin ligase Cbl is activated, and attenuates many of these signals via lysosomal degradation. In cancers where there are mutations in PTK signaling, this communication breaks down, leading to uncontrolled cell proliferation and poor patient prognosis.
During my postdoctoral work in Dr. John Kuriyans lab at UC Berkeley, I am using biochemical assays and X-ray crystallography to better understand the regulation and selectivity of Cbl with respect to its targets. Cbl has a unique activation mechanism, whereby substrate docking is followed by phosphorylation at a conserved tyrosine residue, turning Cbl on. I hypothesize that crosstalk between Cbls tyrosine kinase binding and RING domains dictates its selectivity and regulates substrate kinase activity. PTK signaling is a finely tuned product of evolution, and a greater understanding of how Cbl interacts with its substrates will unveil new possibilities for intervention.
Department of Molecular Biology and Princeton Neuroscience Institute, Princeton UniversityRead more
Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University
Auditory coding contributing to drosophila courtship behavior
Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MassachusettsRead more
Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
Mechanisms of lipid droplet formation, with Robert Farese
Division of Biology: Geological & Planetary Sciences, California Institute of Technology, Pasadena, CaliforniaRead more
Division of Biology: Geological & Planetary Sciences, California Institute of Technology, Pasadena, California
The role of hopanoids in plant-microbe symbioses, with Dianne Newman
A native of rural Pennsylvania, my interest in biology was sparked by a summer research program for high school students on ribosome biogenesis at Carnegie Mellon University. As an undergraduate, I studied biochemistry and philosophy at the University of Notre Dame, where I researched the molecular evolution of bacterial actin-like proteins with Dr. Holly Goodson. I continued my Westward migration to pursue a PhD at UCSF. In my thesis research with Dr. Dyche Mullins, I developed new tools for in vivo imaging of nuclear actin, which I used to discover a role for nuclear actin filaments in the DNA damage response.
As a postdoc I decided to jump across the branches of the tree of life, and I am currently working in the lab of Dr. Dianne Newman at Caltech to determine how the membrane composition of rhizobia, soil bacteria that engage in symbiotic nitrogen fixation in the roots of legume plants, affects their symbiotic fitness and recognition by plant hosts. I am particularly interested in the role of hopanoid lipids, which may be required for bacterial adaptations to environmental stress.
Department of Genetics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MassachusettsRead more
Department of Genetics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
The role of circular RNAs in prostate cancer development and progression, with Pier Paolo Pandolfi
The tremendous advances in DNA and RNA sequencing technologies have recently had a profound impact on our understanding of cancer biology and have revealed the importance of the non-protein-coding RNA molecular “space”. Disregarded for the past 20 years and considered products of aberrant RNA splicing, circular RNAs are nowadays acknowledged as an attractive type of noncoding RNA, probably involved in a multitude of cellular processes and able to play a critical role in human diseases.
The aim of my project is to uncover circular RNAs with diagnostic, prognostic and therapeutic potential in prostate cancer which represents the most common non-cutaneous malignancy and one of the leading causes of cancer-related deaths among men, both in Europe and in the United States. At the same time we aim to elucidate critical properties of this fascinating class of RNAs, opening new horizons for the entire cancer research field.
Department of Biochemistry and Biophysics, University of California, San FranciscoRead more
Department of Biochemistry and Biophysics, University of California, San Francisco
Germline rejuvenation in C. elegans, with Cynthia Kenyon
The survival of a species requires that age must be reset with each generation. How germ cells, the reproductive cells of animals, accomplish this feat remains a fundamental, unsolved question in biology.
Utilizing the genetically-tractable nematode Caenorhabditis elegans, my research aims to identify mechanisms that cleanse the germ lineage of cellular damage and thereby allow for trans-generational rejuvenation. As a JCC fellow in Dr. Cynthia Kenyon’s lab, I have uncovered a regulatory switch that links damage elimination to fertilization and establishes a clean slate for the next generation prior to embryogenesis. Currently, I am exploring the molecular underpinnings of this switch in more detail.
Because molecules that ensure the immortality of the germ lineage might be capable of rejuvenating diverse cell types, I am also testing whether these natural age-reversal strategies can be co-opted in somatic tissues. If so, mechanisms important for germline immortality might provide a promising entry point for reversing whole-organism aging.
Department of Molecular and Cellular Biology, University of California, Berkeley, CaliforniaRead more
Department of Molecular and Cellular Biology, University of California, Berkeley, California
Genetic regulation of multicellularity in a close relative to metazoans
The evolution of regulatory mechanisms to coordinate multicellular development was critical to the origin of animals. Fundamental mechanisms that led to animal multicellularity may also be conserved in the closest living relative of animals, the choanoflagellates, since one species, Salpingoeca rosetta, can transition to a multicellular form called a rosette in a process that is reminiscent of early embryogenesis in animals. To uncover how this multicellular transition is controlled in S. rosetta, we are establishing transgenic and genomic methods that will enable investigating how genes coordinate rosette development. These advances will provide essential tools for exploring the molecular biology of these ecologically and evolutionarily important organisms and potentially illuminate the earliest stages of animal evolution and development.
Radiation Oncology, Stanford University School of Medicine, Stanford, CaliforniaRead more
Radiation Oncology, Stanford University School of Medicine, Stanford, California
Consequences of p53 activation during development, with Laura Attardi
The p53 protein is a transcription factor that becomes activated in response to various cellular stress cues. Once activated, p53 induces target genes involved in apoptosis, cell cycle arrest, senescence and differentiation. Maintaining the correct levels of p53 is critical, since loss of p53 promotes cancer, while increased p53 activity promotes developmental defects and premature aging. To further define the consequences of increased p53 activity, the Attardi lab created a novel mouse model in which p53 is activated during embryogenesis. Intriguingly, this led to a variety of craniofacial and cardiovascular defects. This unique constellation of phenotypes is reminiscent of human CHARGE syndrome, which is caused by mutations in CHD7. I am now using our p53 mouse models to study the cellular and molecular mechanisms by which p53 promotes features of CHARGE syndrome. These studies will further our understanding of p53 as a mediator of developmental disease in addition to its role as a tumor suppressor.
Department of Biology, Massachusetts Institute of Technology, Cambridge, MassachusettsRead more
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts
Elucidating the role of E. coli Lon protease N-domain in substrate recognition and discrimination, with Tania Baker
My primary research interest is studying the molecular basis of the diverse protein-protein interactions that underlie bacterial cell signaling. I am currently focusing on determining the various types of substrate interactions mediated by the E. coli Lon protease to understand how this critical regulator degrades certain proteins during cellular stress. Lon is one of the major proteases that mediates protein quality control via degradation of over half of the unfolded or misfolded proteins in the cell. Additionally, Lon degrades stably-folded regulatory proteins involved in response to several stresses such as DNA damage, heat shock, and oxidation. Using a combination of biophysical and biochemical assays, including electron microscopy, X- ray crystallography, analytical ultracentrifugation, and enzyme kinetics, my current goal is to identify the molecular interactions critical for Lon self-assembly and substrate recognition. With this detailed information, we can begin to understand in greater detail how Lon discriminates among various substrates to regulate critical cellular stress responses and survival.
Department of Human Genetics, University of California, Los AngelesRead more
Department of Human Genetics, University of California, Los Angeles
A novel bulk segregant method to identify natural genetic variants underlying C. Elegans resistance to chemotherapy drugs, with Leonid Kruglyak
Highly effective and commonly used drugs in cancer therapy fail to elicit a response or cause adverse side effects in a significant number of patients. In order to improve the prognosis and treatment of individual patients, it is fundamental to understand the basis of such differences. Most human diseases and traits are influenced by genetic factors. Yet, little is known about the total number of loci underlying differential drug response and how genetic variants confer resistance. In order to gain insights into the genetic and molecular basis of differential response to chemotherapeutic agents, we propose the development of a novel bulk segregant analysis (BSA) strategy in the model organism Caenorhabditis elegans. This methodology will allow us to map with unprecedented speed the natural genetic variants underlying differences in drug response in the context of a whole-organism. Our approach will likely reveal physiologically relevant genetic variants, since it incorporates pharmacological variables such as drug absorption and distribution that cannot be studied in cell lines. To model the effects genetic variants present in populations, we will make use highly divergent C.
elegans wild isolates, thus making also an important step towards understanding phenotypic variation in natural populations.
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of TechnologyRead more
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Investigating mechanisms of immune evasion in autochthonous lung tumors
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
The role of Kcnk3 and membrane potential in adipose tissue thermogenesis
My current research focuses on the molecular mechanisms underlying adipose tissue development and metabolism. In particular, I use genetic and biochemical approaches to identify the molecular differences between the energy-storing white fat and energy-dissipating brown/beige fat in the hope of using those differences to help design therapeutic strategies for the prevention and treatment of obesity.
Brown and beige fat dissipates energy as heat in a process known as non-shivering thermogenesis. The transcriptional regulator Prdm16 was previously identified to facilitate thermogenesis; however, its relevant target genes remain incompletely known. Through ChIP-Seq and RNA-Seq, we have identified a number of potential Prdm16 targets. Among those, I focus on delineating the functions of a rectifying potassium channel Kcnk3 in thermogenesis. Kcnk3 is known to set the plasma membrane potential by generating potassium currents in neurons. I hypothesize that Kcnk3 sets the appropriate membrane potential in thermogenic adipocytes, which may be important for thermogenesis. I will test this hypothesis using fat-specific Kcnk3 knockout mice.
Department of Surgery, University of California, San Francisco, California
Understanding liver bile duct formation to grow biliary tubes in vitro, with Holger Willenbring
Department of Systems Biology, Harvard Medical School, Boston, Massachusetts
Molecular dynamics of oncogene-induced senescence, with Galit Lahav
My current research focuses on the molecular dynamics of oncogene-induced senescence (OIS). By using a set of fluorescent reporters and single-cell time-lapse microscopy, I am trying to understand how variability in oncogenic activity, protein expression levels, etc. are linked to distinct cell fates, i.e., proliferation, transient cell cycle arrest and senescence.
My training began in my hometown, Taiwan, where I received my M.S. in molecular medicine and worked on programmed cell death in C. elegans. I then received my Ph.D. in Chemical and Systems Biology at Stanford supervised by Tobias Meyer. I combined single-cell image analysis, multi-parameter signal profiling, and high-content siRNA screening to understand how growth factor signals are translated by individual cells into a decision to proliferate or differentiate. I joined Galit Lahavs lab at Harvard Medical School for postdoctoral training, and continue my long term interests in cell growth regulations. I expect that the knowledge gained from my postdoctoral work will allow us to understand how cell-to-cell variability at various levels contributes to the establishment of OIS, and explains how OIS is escaped in some cells. It can also be exploited for therapeutic utility to activate cellular senescence in cancer cells.
Department of Cellular and Molecular Pharmacology, University of California, San FranciscoRead more
Department of Cellular and Molecular Pharmacology, University of California, San FranciscoSponsor: Jonathan Weissman
Systemic analysis of the relationship between incRNAs and translation
Long non-coding RNAs (lncRNAs) have recently emerged as key functional molecules in gene regulation, with increasing evidence pointing to a role for lncRNAs in human diseases such as cancer. While the importance of a subset of nuclear lncRNAs in epigenetic and transcriptional gene regulation is well established, lncRNAs are also found in the cytoplasm and may function in different cytoplasmic processes including translational control. In particular, lncRNAs may regulate the translation of other transcripts; or, they may be associated with ribosomes and translated to produce short regulatory “micropeptides”. However, studying the roles for lncRNAs in translation has been hindered by the lack of high-throughput methods to systematically identify lncRNA candidates and probe how lncRNAs act globally to impact translation. Here, I propose a research program that uses a repertoire of genome-wide techniques, combining CRISPR interference and ribosome profiling, to provide fundamental insights into the novel role of lncRNAs in translational control.
Department of Biology, Stanford UniversitySponsor: Judith Frydman
Dissecting the protein folding mechanism by the TRiC chaperonin
Proteostasis is a central mechanism to regulate the health of the cellular proteome. Proteostasis dysfunction has been directly implicated in age-related diseases, including cancer. A central but very poorly understood component of proteostasis network is the eukaryotic chaperonin, TRiC/CCT. TRiC is an essential chaperone that assists folding and assembly of many proteins fundamentally important to cancer, including the tumor suppressors p53, VHL, telomerase as well as other cell cycle regulators. It is, therefore, not surprising that mis-regulation of TRiC is also linked to numerous pathological conditions. Indeed, several TRiC subunits are highly up-regulated in cancer, and their up-regulation is linked to poor prognosis. The paucity of structural and mechanistic knowledge on this complex has hindered the development of therapeutic strategies targeting TRiC. Therefore, my research in the Frydman lab focuses on closing this gap by defining the molecular basis of human TRiC to fold the key disease-linked proteins. I am interested in combining biochemical and structural methods to elucidate the underlying principles by which TRiC recognizes and folds proteins. I anticipate the result of this work will provide mechanistic insights relevant to human diseases.
Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MassachusettsRead more
Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts
Probing the dynamics of the eukaryotic replicative helicase, with Johannes Walter
The eukaryotic helicase CMG (Cdc45+MCM2-7+GINS) is the molecular machine that unwinds dsDNA during replication. Although CMG plays a central role in replication, key aspects of its dynamics are poorly understood. It has been proposed that before activation, loaded MCM complexes can slide on dsDNA. However, this phenomenon has not been examined under physiological conditions and its functional significance remains unclear. In addition, how the CMG helicase operates under conditions of replicative stress is not understood.
To address these questions, I will perform single-molecule imaging of MCM2-7 complexes in completely soluble Xenopus egg extracts, which were pioneered in my sponsors laboratory.
In Aim 1 I propose to probe the dynamics of individual dsDNA-bound MCM complexes prior to replication initiation. In particular I seek to determine whether dormant MCM complexes can slide on dsDNA in physiological conditions. In Aim 2 I propose to investigate the fate of dormant MCM complexes upon their collision with oncoming replication forks. In Aim 3 I propose to study the dynamics of the helicase after its uncoupling from the replicative polymerase, and seek to determine how the helicase activity is regulated by the activation of the DNA damage checkpoint.
Vollum Institute, Oregon Health and Science University, Portland OregonRead more
Vollum Institute, Oregon Health and Science University, Portland Oregon
Structure of the NR1-NR2 subtype of the NMDA receptor in the open state, with Eric Gouaux
Department of Human Genetics, University of Utah, Salt Lake City, Utah
Co-option of endogenous retroviruses for host immune responses, with Cedric Feschotte and Nels Elde
My current research is focused on the biology and evolution of transposons, which are DNA parasites that constitute over half of the human genome. Specifically, I am investigating the long-standing hypothesis that transposon activity is a major mechanism underlying the evolution of gene regulatory networks.
I became interested in evolutionary biology as an undergraduate at UC San Diego, where I worked with Hopi Hoekstra studying the volatile history of rodent placental proteins. I continued studying placental evolution as a graduate student at Stanford University with Julie Baker, where we found that transposons may contribute to pregnancy-related adaptations by functioning as species-specific regulatory elements. Inspired by the potential for transposons to drive rapid evolutionary change, I decided to do my postdoc in the laboratories of Cedric Feschotte and Nels Elde at the University of Utah, where I am studying the role of transposons in shaping the evolution of human innate immune responses. Outside the lab, I enjoy the vast outdoor recreational activities in Utah, including hiking, skiing, and canyoneering.
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CaliforniaRead more
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California
Forecasting evolution of drug resistance in hepatitis C virus, with Ren Sun and James Lloyd-Smith
I am broadly interested in the evolution of drug resistance. For example, how does the distribution of fitness effects influence the predictability of evolution? What is the role of epistasis in the adaptation to higher drug resistance? How can we integrate in vitro fitness data with in vivo models to design personalized drug therapy for patients?
To address these questions, I combine high-throughput in vitro fitness measurements with mathematical models of viral dynamics to predict the evolution of drug resistance in Hepatitis C Virus and HIV. Using deep sequencing, I perform high-throughput fitness assays for a library of mutant viruses to systematically explore epistasis and evolutionary pathways towards drug resistance. By combining empirical fitness landscapes with mathematical models of within-host viral dynamics and pharmacokinetics/pharmacodynamics, I build a quantitative framework to predict viral evolution and minimize the risk of drug resistance during therapy. The principles for rational design of antiviral therapy will inform patient-specific therapy of targeted cancer drugs.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical SchoolRead more
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School
Molecular messages in algal-bacterial symbiosis
Division of Signaling and Gene Expression, La Jolla Institute for Allergy & ImmunologyRead more
Division of Signaling and Gene Expression, La Jolla Institute for Allergy & ImmunologySponsor: Anjana Rao
TET loss-of-function and R-loops-mediated genomic instability in cancer
The TETs (TET1, TET2, TET3) are epigenetic enzymes regarded as responsible for active and passive DNA demethylation, and are involved in a wide array of physiological and pathological cellular responses.
I have performed my Ph.D training in Prof. François Fuks’ laboratory in Belgium at the time that TET function was discovered by the team of Prof. Anjana Rao. Applying proteome and genome-wide approaches, we found that the most potent partner of TETs is the glycosyltransferase OGT (Deplus*, Delatte* et al., Embo, 2013), and I recently discovered that Tet is responsible for RNA hydroxymethylation in drosophila (Delatte et al., Science, 2016).
Therefore, I naturally couldn’t resist joining Anjana’s lab where I am now investigating the roles of TETs and hydroxymethylcytosine in genomic instability and cancer. I am also fascinated by the advances in next-generation sequencing, and am developing novel methodologies to map epigenetic modifications, but also identify diverse hallmarks of cancer such as DNA breaks or aberrant DNA:RNA structures.
Outside of the lab, I enjoy surfing, hiking, and particularly love watching movies with friends.
Department of Cellular and Molecular Medicine, University of California, San DiegoRead more
Department of Cellular and Molecular Medicine, University of California, San Diego
Investigating dynein-mediated viral transport, with Samara Reck-Peterson
I am interested in cellular transport, or in other words, how things, like organelles, mRNA, and viruses are shuttled around the cell. In the Reck-Peterson lab, we study the microtubule-associated motor protein, dynein. Dynein is a large, muti-subunit complex that walks towards the center of the cell along microtubule tracks. I am particularly interested in understanding how other proteins, referred to as dynein-adaptors, regulate dynein function and specificity for cellular cargo. In our lab, we take a two-pronged approach to understanding dynein biology. First, we use techniques like single molecule-fluorescence microscopy and electron microscopy to study dynein function on a mechanistic level. Secondly, we use mass spectrometry to conduct proteomic screens to identify novel proteins that interact with dynein.
Laboratory of Genetics, The Salk Institute for Biological StudiesSponsor: Fred Gage
Investigation of inflammation in Parkinson's
Department of Molecular and Cellular Biology, Harvard University, Boston, MassachusettsRead more
Department of Molecular and Cellular Biology, Harvard University, Boston, Massachusetts
Novel signaling peptides in zebrafish development, with Alexander Schier
The goal of my project is to identify and characterize novel signals regulating development. Many of the processes taking place during development are controlled by a handful of well-characterized signaling pathways. This observation has led to the belief that most, if not all, of the major developmental signals are known. However, recent genomics projects have identified numerous uncharacterized genes, several of which encode short secreted peptides. A zebrafish mutant generated in one of these peptides, EndE, has a dramatic developmental phenotype, where the embryo forms little or no heart tissue. This suggests that EndE regulates the specification and/or migration of cardiac precursor cells. I will investigate the role of EndE in cardiac development and identify its receptor (Aim 1). Additionally, I will generate mutants for several other novel secreted peptides and analyze their phenotypes (Aim 2). My project will elucidate the role of a novel regulator of heart formation and identify new developmental signaling molecules.
Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
Uncovering mechanisms that control cell sorting during development, with Jim R. Priess
I am studying development in the model organism C. elegans to discover novel cell sorting regulators. During development cells sort to associate with other cells of the same type so they are in the correct place to form tissues. From studies in other organisms it is clear that different tissues use different genes for cell sorting. These include genes involved in cell attraction, repulsion and adhesion, which are also mis-regulated in many cancers. Understanding novel cell sorting regulators will help us understand what may be causing abnormal cell behaviors in cancerous tissues.
I look specifically at sorting of cells in the C. elegans embryo that develop to form part of the digestive tract, the pharynx. These cells form an interior aggregate, while other cells, such as muscles are excluded from this region. By identifying mutants defective in this process I will discover what genes regulate cell sorting in C. elegans and may also influence cell behaviors in humans.
Department of Pathology & Developmental Biology, Stanford University School of Medicine, Stanford, CaliforniaRead more
Department of Pathology & Developmental Biology, Stanford University School of Medicine, Stanford, California
Characterization of a novel 4 MDa oncogenic complex, with Gerald Crabtree
Recent genome-wide sequencing studies have revealed that genes encoding subunits of SWI/SNF-like BAF complexes are among the most frequently mutated in human cancers. Indeed over 20% of all human cancers have mutations in the subunits of these complexes. I have found that oncogenic subunits of this complex also form a much larger 4 MDa assembly that has been unappreciated to date, raising the question of which assembly is mediating tumor suppression by these complexes. I have also found that this larger complex is characterized by the specific assembly of three subunits, which will allow me to specifically characterize this 4 MDa complex at a biochemical and genetic level. One of these subunits is BAF180 (PBRM1) and my initial results indicate oncogenic mutations in this complex dominantly interfere with the oligomerization of the complex, raising the intriguing model that BAF180 is the keystone subunit of this oncogenic complex. The hypothesis that the 4 MDa complex targets a unique repertoire of chromatin-mediated, tumor suppressor processes will be tested by mass spec and genome-wide analyses. The work I propose will lead to a mechanistic understanding of cancer susceptibility genetics in the context chromatin-mediated control of gene expression.
Department of Neurobiology, Harvard Medical School, Boston, MassachusettsRead more
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts
Multilingual neurons: GABA corelease from cholinergic basal forebrain neurons, with Bernardo Sabatini
Neurons are typically thought to release a single fast neurotransmitter, though a growing number of examples of neurotransmitter corelease are being discovered. Our lab has found preliminary evidence that the acetycholine (ACh) releasing neurons of the basal forebrain (BF) also release GABA. The BF is the primary source of Ach neurotransmission throughout the central nervous system, and is responsible for modulating attention, arousal, and the cognitive deficits that underlie Alzheimer’s disease. In this proposal, I outline a research plan to characterize the extent of GABA/ACh corelease from BF neurons throughout the cortex. I will then explore the presynaptic mode of ACh/GABA corelease to determine if they are released from the same or separate populations of synaptic vesicles. Finally, I will test the functional importance of this projection in shaping cortical activity by performing in vivo recordings from the cortex awake, behaving mouse during optogenetic activation of ACh-releasing BF neurons. The contribution of GABA will be explored by comparing recordings from wild-type mice with mice that lack GABA release specifically in ACh-releasing BF neurons. The results of these experiments will provide novel insight into the role of GABA/ACh corelease for BF function.
Department of Genetics, Stanford University, Stanford, California
Integrated omics of malignant transformation by breast cancer genes, with Michael Snyder
Through my clinical work with oncology patients I became acutely aware of how few interventions we are able to offer patients to prevent cancer. Even patients with inherited syndromes that confer a near-certainty of developing cancer have few, often unappealing, options to actually prevent cancer. This motivated me to investigate molecular mechanisms of the earliest steps of malignant transformation. I chose to study the genes causing inherited breast cancer because each one constrains the malignant phenotype of breast cells, an effect that can be modeled in vitro.
These ideas led me to team up with my advisor Dr. Michael Snyder at Stanford who has pioneered multiple high-throughput omics technologies to densely profile biological systems. These tools allow for an unprecedented window into cellular dynamics driving malignant transformation. I am particularly interested in how genomic aberrations in non-coding DNA elements can unlock transcriptional programs that drive malignancy. The hope is to uncover molecular switches that can be targeted to prevent cancer onset.
Department of Genetics, Brigham and Womens Hospital, Boston, MassachusettsRead more
Department of Genetics, Brigham and Womens Hospital, Boston, Massachusetts
The role of SASP regulator GATA4 in senescence and cancer, with Stephen Elledge
The majority of cancer therapeutics currently used result in DNA damage that can trigger cell death or senescence in cancer cells and in healthy neighboring cells. Understanding how transformed cells and otherwise healthy cells induce or evade senescence pathways in response to cancer therapies is the major interest of my research in order to better understand therapeutic resistance mechanisms.
I was born and raised in New Hampshire and received my BS in biochemistry from the University of Vermont. My research career started in Jim Vigoreauxs lab where I investigated mechanisms of energy transport in Drosophila flight muscle. As a graduate student in Sharon Cantors lab at the University of Massachusetts Medical School I studied DNA repair pathways and mechanisms that lead to chemo-resistance in hereditary forms of ovarian cancer. Currently, I am working with Dr. Stephen Elledge in the Department of Genetics at Harvard Medical School. Here I aim to elucidate the molecular circuitry that controls cellular senescence.
Department of Biology Massachusetts Institute of Technology, Cambridge, MassachusettsRead more
Department of Biology Massachusetts Institute of Technology, Cambridge, Massachusetts
Quantitative dissection of how genome organization impacts gene expression with Michael Laub
F.M. Kirby Neurobiology Center, Childrens Hospital Boston, Boston, MassachusettsRead more
F.M. Kirby Neurobiology Center, Childrens Hospital Boston, Boston, Massachusetts
Mechanism for activating the clearance of damaged axonal mitochondria, with Thomas Schwarz
One crucial pathway that marks damaged mitochondria for removal involves constant mitochondrial import and degradation of the PTEN-induced kinase 1 (PINK1), a protein compromised in a hereditary form of Parkinsons disease. My current research focuses on how the PINK1 pathway is activated in the axonal compartment of neurons.
Growing up as the daughter of two math and science teachers my curiosity for science was nurtured from the very beginning. I pursued my interest for the workings of the cells in our body by studying Molecular Medicine in Freiburg/Germany, finally joining the lab of Nikolaus Pfanner and Chris Meisinger. During my PhD there I demonstrated that mitochondrial functions such as energy production and metabolite transport could be controlled by phosphorylation of the import pathway for mitochondrial proteins.
Having fallen in love with mitochondria, I am continuing my research as a Post-Doc in the lab of Tom Schwarz and am extending my research on protein import towards transport of mitochondria, mitochondrial proteins and RNA in neurons and implication of transport in Parkinsons disease.
Department of Molecular and Cell Biology, University of California, Berkeley, CaliforniaRead more
Department of Molecular and Cell Biology, University of California, Berkeley, California
Illuminating novel actin cytoskeletal dynamics through a bacterial pathogen, with Matthew Welch
An array of actin modulators promotes actin filament assembly, disassembly, and organization. However, a detailed understanding how this vast network of factors work in concert to precisely regulate actin dynamics is at best incomplete. Many insights into actin regulation have been derived through examining how microbial pathogens manipulate the actin cytoskeleton during infection. The bacterial pathogen Mycobacterium marinum, a close relative of Mycobacterium tuberculosis, has the rare ability to stimulate actin-based motility in the host cytoplasm. However, the bacterial and host factors that contribute to this phenomenon are largely unknown.
Circumstantial evidence suggests M. marinum recruits the actin nucleation promoting factors WASP and N-WASP through an unusual ability to synthesize phosphorylated phosphoinositol (PIP) lipids. Subsequently, M. marinum activates WASP and N-WASP to nucleate actin filaments through an unfamiliar pathway. The goal of this work is to define M. marinum actin-based motility to further illuminate actin regulation at cellular membranes.
Department of Biology, Stanford University, Stanford, CaliforniaRead more
Department of Biology, Stanford University, Stanford, California
Spatiotemporal dissection of BDNF/TrkB in circuit assembly, with Liqun Luo
My passion in understanding the transcriptional mechanism underlying neurological disorders was inspired by my Ph.D. mentor, Dr. Huda Zoghbi, at Baylor College of Medicine. Currently, I work with Dr. Liqun Luo at Stanford University and focus on exploring the neurobiology of Rai1, a dosage-sensitive gene responsible for most phenotypes in Smith-Magenis syndrome (SMS). SMS is a neurodevelopmental disorder characterized by multiple congenital anomalies and many autistic features. Little is known about how Rai1, a putative transcriptional regulator, causes the neurological symptoms. I will create several mouse models to dissect the function of Rai1 in the mouse brain, and explore the possible therapeutic strategy for SMS.
Department of Pharmaceutical Chemistry, University of California, San Francisco, CaliforniaRead more
Department of Pharmaceutical Chemistry, University of California, San Francisco, California
Within and between-cell effects of driver mutations on breast tumor fitness, with Zev Gartner
I am applying quantitative engineering approaches to study collective cell phenomena in cancer. Different cells in tumors develop different sets of mutations over time, creating a range of cell clones. One view of the role of cancer mutations is that they enable a small number of progressively malignant clones to take over the tumor one after another. However, mutations can have more complicated effects on tumor progression because their outward effects on the growth of a clone can depend on who their neighbors are. Therefore, I want to understand how cancer mutations affect the overall fitness of tumors by directly measuring it, not just in the cells that contain mutations, but also in neighboring cells. My research aims to shed light on how benign tumors make the transition to proliferative, invasive tumors; perhaps uncovering an Achilles heel to the manipulation of normal cells by mutant ones, leading to new types of cancer therapies.
Department of Genetics, Harvard University, Boston, Massachusetts
The role of organ communications in stem cell aging, with Norbert Perrimon
Adult stem cells are critical for maintaining homeostasis by repairing damaged tissues; however, this regenerative capacity of stem cells is affected with age, resulting in tissue degeneration. Age-related perturbations in stem cells are caused by changes in the intrinsic properties of the stem cells, in their niches and in the systemic milieu. In recent years, much has been learned about the pathways that control stem cell fate, lineage and proliferation. However, we know little about the mechanisms underlying age-related changes in stem cells. During my postdoctoral studies, I will investigate the mechanisms influencing the aging process of Drosophila midgut stem cells. In Aim1, I will determine the translatome of stem cells and their progenies during aging and regeneration. In Aim2, I will investigate the roles of inter-organ communication in stem cell aging and identify muscle-derived factors that coordinate gut stem cells aging with systemic aging. Finally, in Aim3, I will perform an unbiased genetic screen using transgenic RNAi lines to identify muscle-derived factors that influence gut stem cells aging. Together, these studies will identify regulatory networks affecting stem cell aging and provide novel insights for age-related diseases such as cancer.
Department of Biological Chemistry, University of California, Irvine, School of MedicineRead more
Department of Biological Chemistry, University of California, Irvine, School of MedicineSponsor: Chang Liu
Using synthetic biology to study the mitochondria
The mitochondrion is a subcellular organelle that is the center of energy production, calcium signaling, apoptosis and redox balance for the cell. Therefore, many diseases and normal aging run their molecular course through the mitochondrion. Uniquely, the mitochondrion contains its own DNA and makes RNA and proteins independently from the rest of the cell. This orthogonal system had presented a problem for studying the mitochondrion as the usual genetic tools of the nuclear genome are not available. However, I am using the tools of synthetic biology to allow specific interrogation of mitochondrial protein synthesis in healthy and diseased human cells.
In addition to studying mitochondrial protein synthesis, I am developing the yeast mitochondrion as a platform for synthetic biology in order to greatly expand the genetic code and to speed up laboratory evolution. These tools will allow creation of novel therapeutic biopolymers and proteins.
Department of Biochemistry & Biophysics, University of California, San Francisco, CaliforniaRead more
Department of Biochemistry & Biophysics, University of California, San Francisco, California
Mechanisms of VCP-mediated cellular degeneration, with Graeme Davis
I am exploring links between the genetic and molecular causes of neurodegenerative diseases, such as ALS, Alzheimers and Parkinsons disease. A common hallmark of almost all degenerative diseases is the progressive accumulation of protein aggregates. Autophagy-lysosome mediated degradation is the major pathway that clears aggregates from the cytoplasm and autophagy defects are associated with many degenerative diseases. Using Drosophila as a model system, I am studying how the autophagy-lysosome pathway functions normally and how this pathway is affected by degenerative disease causing mutations in both neurons and muscles. Additionally, I am studying how extrinsic factors, such as sleep deprivation, affect the autophagy-lysosome system in the context of neurodegenerative diseases.
Laboratory of Membrane Biology and Biophysics, The Rockefeller UniversityRead more
Laboratory of Membrane Biology and Biophysics, The Rockefeller UniversitySponsor: Jue Chen
Structural and mechanistic studies of multidrug resistance mediated by MRP1
Resistance to chemotherapeutic drugs is a major obstacle in the successful treatment of many different forms of cancer. This so-called multidrug resistance is often mediated by a class of proteins known as ABC transporters. These proteins reside in the plasma membrane and actively pump molecules out of the cell by utilizing the energy of ATP binding and hydrolysis. Some ABC transporters recognize and extrude anticancer compounds before they are able to kill the cancer cells, leading to drug resistance and treatment failure.
My project seeks to gain a better mechanistic understanding of these transporters and their role in multidrug resistance by utilizing a combination of structural and functional studies. My focus will be on the ABC transporter known as multidrug resistance protein 1 (MRP1). If we can better understand how these proteins are able to recognize and transport their drug substrates, we will be able to develop ways to block or circumvent their function during cancer treatment. If successful, these studies will not only further our knowledge of ABC transporter biology, but they will also lay a framework for combating multidrug resistance in cancer patients.
Department of Psychiatry, University of California, San FranciscoRead more
Department of Psychiatry, University of California, San FranciscoSponsor: Frank Loren
Neural activity underlying individual variability in spatial decisions
Memory informs how animals interact with the world. It provides an expectation of the future based upon past experience. With navigation, animals draw upon a memory of their surroundings to inform their decisions. The hippocampus is critical for spatial decision-making by providing multiple ways to recall surroundings. Yet, why the hippocampus has multiple recall strategies remains unknown. To test the hypothesis that different recall strategies provide the substrate for individual variability, I will explore the behavior and hippocampal neural activity of both male and female rats during different spatial tasks. Beyond just recording the differences between animals, I will also specifically block hippocampal recall activity to determine their necessity for individual behavior. Studying individual decision-making will explore the range of neural computations that are consistent with normal functioning, and further our understanding of the complex relationship between the internal representation of the world and its external manifestations
Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller UniversiyRead more
Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller Universiy
Structural and mechanistic principles of the HCN pacemaker channel
Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California, BerkeleyRead more
Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California, BerkeleySponsor: Kristin Scott
Maturation of neural circuits for memory
Adult behavior is the product of neural circuits that are wired during development and modified by experience. However, the mechanisms by which neural activity in early development affects circuit maturation to shape behavior remain poorly understood. My research investigates how neural activity in circuits for memory matures and sculpts learned behaviors. Using in vivo calcium imaging, genetic techniques and behavioral analyses in the Drosophila model system, I am characterizing developmentally regulated spontaneous neural activity in brain regions critical for learned behaviors and investigating how this activity shapes mature learned behaviors. I aim to identify molecular changes that trigger the maturation of memory circuitry and behavior. This research will increase our understanding of a fundamental mechanism relevant for normal brain development and may provide insights for translational research into its pathological misregulation in disorders of the nervous system.
Department of Physiology, University of California, San Francisco, CaliforniaRead more
Department of Physiology, University of California, San Francisco, California
Using unique crocodilian physiology to probe somatosensation, with David Julius
The somatosensory system transduces physical and chemical stimuli from the periphery to the CNS to mediate the senses of touch, temperature, proprioception, and pain. However, there is little information regarding the molecular signaling mechanisms of various mechanical stimuli. Activation of mechanosensitive fibers by injury represents a major source of pain, and thus a greater understanding of how these fibers are activated under normal (acute) and pathophysiological (chronic) pain states is an important goal at both basic and translational levels.
To address this important problem, I shall exploit an unconventional model system with exceptionally acute mechanosensation: the crocodilians, whose jaws are covered in discrete tactile receptors. Recent physiological work suggests the receptors mediate a sense of touch exceeding that of human fingertips, providing a high-resolution tactile portrait of surrounding environments. Following recent work in the sponsor’s lab identifying novel, highly-sensitive infrared (heat) ion channel subtypes in rattlesnakes and vampire bats, we propose to exploit state-of-the-art transcriptome profiling to uncover molecules that endow crocodilian sensory ganglia with exquisite mechanosensitivity. Identified molecules will be examined in more tractable genetic systems (e.g. mice) for further functional analyses, with the goal of uncovering molecular mechanosensory mechanisms in mammals under normal and/or pathophysiological pain states.
Laboratory of Genetics, The Rockefeller University, New York, New YorkRead more
Laboratory of Genetics, The Rockefeller University, New York, New York
Decoding neuromodulatory control of sleep and wakefulness in Drosphila, with Michael Young
The application of Drosophila as a model system has led to many fundamental discoveries concerning the regulation of sleep and wakefulness, including conserved molecular pathways and neural circuits that parallel human studies. Superimposed on the neural circuit wiring diagram are the neuromodulators – biogenic amines and neuropeptides, which are key mediators of the opposing states of sleep and wakefulness. Preliminary research has suggested a novel neuromodulatory circuit in Drosophila that signals arousal and antagonizes sleep. In this proposal, a set of circuit tracing experiments is planned to map this circuit and a novel imaging tool will be developed to visualize peptidergic modulation during states of sleep and wakefulness. In addition, whole-genome transcriptional and translational profiling experiments are proposed to investigate the molecular features of brains under neuromodulatory control. The long-term goal of this proposal is to gain a deep understanding of neuromodulatory processes on genetic, circuit and molecular levels that affect sleep/wake regulation. These studies may also shed light on broader principles of brain function, such as consciousness and memory.
Gladstone Institute of Neurological Disease, The J. David Gladstone Institutes, University of California, San Francisco, CaliforniaRead more
Gladstone Institute of Neurological Disease, The J. David Gladstone Institutes, University of California, San Francisco, California
Contribution of basal ganglia-recipient thalamus to cortical motor plans, with Anatol Kreitzer
The proper execution of voluntary movements is a critical function of the nervous system. In mammals, the activity in the motor cortex that drives voluntary movements is thought to be controlled by a neuronal circuit in which excitatory thalamic inputs to motor cortex are regulated by inhibition from the basal ganglia. While the basal ganglia are implicated in motor function due to severe motor deficits following basal ganglia degeneration, the function of basal ganglia remain controversial, with some theories suggesting a role in action selection and others indicating a role in controlling the amplitude or gain of movements. As such, contributions of the basal ganglia-recipient thalamus (BGThal) to movementrelated activity in motor cortex are poorly understood. I propose to characterize how activity is organized in BGThal and motor cortex by recording from these structures in mice performing a forelimb movement task. Next, I will use recently developed optogenetic tools to selectively suppress BGThal activity to see how BGThal contributes to the magnitude and temporal precision of movement-related activity in the motor cortex. These experiments will help us begin to understand at a mechanistic level how the basal ganglia, thalamus, and motor cortex work together to produce voluntary movements.
Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, New YorkRead more
Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, New York
Exploring the mechanism of skin stem cell regulation in skin wound repair, with Elaine Fuchs
Department of Chemical and Systems Biology, Stanford UniversitySponsor: Joanna Wysocka
Prion dynamics of transcription factors control cellular differentiation
I am interested in the prion dynamics of transcriptional regulators during human cell development. Lots of transcription factors contain low-complexity domains, which can drive the prion/granule formation. However, little is known about the prion functions or mechanisms of human transcriptional regulators. In our preliminary results, I found that some transcription factors form prions/granules at specific stages of the human neural crest differentiation process and the prions disappear rapidly afterwards. Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm cell layer, and in turn give rise to a diverse cell lineage. We hypothesize that the observed prion dynamics of transcription factors are crucial to the neural crest differentiation. As a postdoc in the Wysocka lab at Stanford, I will investigate the regulation factors of the observed prion dynamics as well as the molecular and developmental roles of these prions related to transcription regulation.
Department of Medicine and Rheumatology, University of California, San Francisco, CaliforniaRead more
Department of Medicine and Rheumatology, University of California, San Francisco, California
The role of T Cell receptor-induced sulfenylation in CD4+ T Cell differentiation, with Arthur Weiss
The production of reactive oxygen species (ROS) is required for T cell activation and expansion. Dysregulation of ROS-producing NADPH oxidase or mitochondria causes the alteration of T cell function in several clinical diseases, including cancers. ROS modifies T cell receptor (TCR) signaling cascades, in part, through a post-translational modification known as protein sulfenylation. Deprivation of ROS-mediated sulfenylation impaired T cell proliferation and activation, yet elevated ROS rates in tumor microenvironment also suppressed T cell mediated anti-tumor responses. Though the importance of ROS in TCR signaling and hematopoietic malignancies is apparent, little is known about the roles of ROS-mediated sulfenylation in T cell signaling. We propose to introduce a new chemical probe to detect changes in protein sulfenylation directly in primary T cells. We will elucidate how the sulfenylation of key substrates is controlled by ROS generation and TCR stimulation, and also explore biological impacts of non-sulfenylateable key substrates in T cell function and TCR signaling.
Department of Biological Structure, University of Washington, Seattle, Washington
Structural study of porcupine, a membrane protein essential to Wnt function, with Wenqing Xu
Im trying to investigate three dimensional structures of proteins those play important roles in Wnt signaling pathway. Aberrant regulation of Wnt proteins and their signal-transduction cascades are associated with the development of many diseases including some cancers. The aims of my research are to explain the molecular mechanism for Wnt secretion and downstream regulation.
Im from China, and I got my PhD degree at Tsinghua University. I used to be a structural biologist, and now Im still a structural biologist, because I think this is a good way for me to understand many biological processes at molecular level. I mainly focus on structural and biochemical studies of important proteins related with human diseases, and I really hope my research will help people better understand and fight with diseases. Now Im working as a postdoc in Seattle, a beautiful and romantic city, and I think I will enjoy my research and enjoy my life!
Laboratory of Cell Biology & Genetics, The Rockefeller University, New York, New YorkRead more
Laboratory of Cell Biology & Genetics, The Rockefeller University, New York, New York
Can telomere attrition initiate chromosome shattering?, with Titia de Lange
I am researching the causes of complex, chromosome rearrangements and hypermutation in cancer genomes. Recently uncovered by next generation sequencing, these catastrophic phenomena are understood to play a major part in cancer progression, but the instigating mechanisms are not clear. Telomere crisis occurs during tumorigenesis when depletion of the telomere causes chromosome to chromosome fusions. These fusion events result in the formation of dicentric chromosomes, which are known to be destabilized during cell division. I hypothesize that these fusion events can precipitate chromosome fragmentation and thus fuel more complex chromosome rearrangements and hypermutation. I am using genetic and cell biological techniques, including high resolution time-lapse imaging, to investigate the immediate fate of these fused chromosomes, as well as next generation sequencing to identify the genomic consequences of their ultimate resolution.
Department of Bioengineering and Therapeutic Sciences, University of California, San FranciscoRead more
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco
My current research aims to explore how DNA regulatory elements influence human development and disease. I am particularly interested in identifying novel enhancers that regulate brain development and identifying mutations within them that lead to neurodevelopmental diseases.
I was born in Germany, where I studied Biology at the University of Goettingen and the University of Kiel. I then came to the US to pursue my Ph.D. in Human Genetics at the University of Utah. My graduate research in the lab of Dr. Mario Capecchi involved examining the role of Hoxa1, a homeobox transcription factor, in early brain development. This sparked my interest in the field of neuroscience and especially in development of the nervous system. I performed a postdoc in Dr. Liqun Luos lab at Stanford to study the connectivity of individual neurons in the brain. For my current postdoc in Dr. Nadav Ahituvs lab at UCSF, I am focusing on identifying gene regulatory elements that are involved in brain development and examining how changes in the genomic regulatory code can lead to specific phenotypes. Outside the lab, I enjoy the various outdoor activities that the Bay Area has to offer.
Department of Biology, Massachusetts Institute of Technology
Defining the landscape and function of pseudouridines in pre-mRNA
Laboratory of Mammalian Cell Biology and Development, The Rockefeller UniversityRead more
Laboratory of Mammalian Cell Biology and Development, The Rockefeller UniversitySponsor: Elaine Fuchs
Dissecting the immune evasion mechanisms of tumorigenic stem cells
My research interest is to harness the power of immune system to combat cancer. This goal requires sophisticated understanding in both immunology and cancer biology. My prior graduate training has equipped me with extensive knowledge in immunology, and showed me how the immune system evokes robust and multilayered responses to defend our body against infections. However, compared to the vigorous response to infections, the immune system often becomes incompetent when it encounters cancer, especially malignant tumors. My goal during the fellowship period is to develop a cancer model in which I can trace the co-evolution between tumor-initiating stem cells and immune system, ultimately to the point of evasion of immune surveillance, so that I can identify the root of the blunted ant-tumor immune response during the cancer progression. With Dr. Fuchs’ expertise in epithelial stem cells and cancers, and my background in immunology, I feel that I’m uniquely poised to tackle this fascinating problem.
Department of Cellular and Molecular Biology, University of California, BerkeleyRead more
Department of Cellular and Molecular Biology, University of California, Berkeley
Pathogen-driven evolution of inflammasome genes
Department of Neurosciences, University of California, San DiegoRead more
Department of Neurosciences, University of California, San Diego
Top-down modulation of visual cortex during attention, with Massimo Scanziani
My general interest is how visual information interacts with non-visual information such as cognitive states to create our visual perception. In the lab of Massimo Scanziani, I am specifically focusing on how attention impacts visual processing in the mouse primary visual cortex. In humans and other primates, attention has been shown to increase the response of visually responsive neurons. It has been suggested that this modulation is mediated by feedback connections arising from higher cortical areas, yet the circuits and mechanisms remain poorly understood.
By using various in vivo and in vitro techniques available for the mouse, I plan on working out the cellular components of the circuit and determining its impact on the animals behavior during a task that requires attention. Through this study, I hope to advance our understanding of the basic principles of how cognitive states influence sensory perception.
Laboratory of Bacteriology, The Rockefeller University, New York, New YorkRead more
Laboratory of Bacteriology, The Rockefeller University, New York, New York
Self vs. non-self discrimination during CRISPR-Cas adaptive immunity, with Luciano Marraffini
A hallmark of immune systems is the ability to selectively recognize and destroy invading agents while ignoring the hosts’ own molecular milieu. Remarkably, CRISPR-Cas systems provide single bacterial cells with adaptive immunity by cleaving the nucleotides of previously encountered invaders based on sequence-specific RNA guides. The mechanisms ensuring that these molecular memories are exclusively created from non-self, invading elements are unknown.
I study adaptation, the first phase of CRISPR-Cas immunity, whereby short spacer sequences of invading DNA are inserted into CRISPR loci. Specifically, I am identifying and characterizing the factors that influence adaptation and allow bacterial hosts to selectively generate spacers from foreign viruses and plasmids. This work will lead to a better understanding of how bacteria have solved a fundamental immunological problem and could provide an additional foundation for the development of CRISPR-Cas-derived technologies.
Department of Molecular and Cell Biology, University of California, Berkeley, CaliforniaRead more
Department of Molecular and Cell Biology, University of California, Berkeley, California
Intra and trans-cellular mitochondrial communication in Parkinsons disease, with Andrew Dillin
Just like people, cells have to deal with stress. I study how stressed cellular organelles such as mitochondria communicate with the nucleus, and how this stress response is coordinated in normal settings and dysregulated in disease.
I studied genetics as an undergraduate at the University of California, Berkeley, and then worked at Sangamo BioSciences to help develop human genome editing with engineered nucleases. I was then an NSF Fellow in the Tetrad PhD program at the University of California, San Francisco, where I worked in Christine Guthries laboratory. There, I studied how pre-mRNA splicing is regulated in particular, how the cell coordinates a pre-mRNAs transcription and its splicing. My interest in how discrete molecular processes are integrated inside the cell continues during my postdoctoral fellowship in Andrew Dillins laboratory, where I am studying a remarkable pathway called the mitochondrial unfolded protein response. In this pathway, nuclear-encoded mitochondrial protein chaperones are upregulated in response to signals from mitochondria experiencing proteotoxic stress. I am using a disease-in-a-dish model that combines human stem cell technology with genome editing approaches.
Department of Molecular and Cell Biology, Harvard University, Cambridge, MassachusettsRead more
Department of Molecular and Cell Biology, Harvard University, Cambridge, Massachusetts
Neuronal control of suckling behavior in newborn rodents, with Catherine Dulac
My research investigates the neural circuits that control instinctive behavior. Previously, my work focused on the innate active sensing behaviors of rodents that dominate exploration and social interactions. This work has led me to focus on questions that involve the nature of the motivational and descending drives that enable animals to generate robust and instinctive motor patterns in the appropriate context. With the expertise of the Dulac Laboratory, I hope to provide insight into these questions by defining the roles of specific, molecularly-defined cell types and neuronal circuit connectivity patterns that relate to such control. I hope to provide a unique perspective that stems from a background in engineering and the neural control of movement.
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MassachusettsRead more
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts
Live cell imaging of chromatin supercoiling dynamics in human cells, with Sunney Xiaoliang Xie
I received my BS in Biochemistry from Susquehanna University and my Ph.D. in molecular biophysics in Professor Scott Baileys lab at Johns Hopkins University. Broadly speaking, I am interested in exploring the structure-function relationship of biological macromolecules. For my Ph.D. thesis, I used different structural and biochemical methods to investigate the mechanism by which bacteria use their CRISPR immune system to destroy foreign DNA.
In my postdoc with Professor Sunney Xie at Harvard University, my research focuses on the effects of chromatin structure on eukaryotic gene expression. More specifically, I am interested in understanding the dynamics of DNA supercoiling at a single-cell level. Outside the lab, I enjoy playing soccer and going on hikes.
Department of Molecular and Cellular Biology, Havard UniversityRead more
Department of Molecular and Cellular Biology, Havard UniversitySponsor: Catherine Dulac
Characterizing the thermoregulatory circuits that control animal behavior
Thermoregulation is fundamental for survival; even slight changes in body temperature have a dramatic effect on vital processes such as sleep, appetite, and thirst, and during an immune response, febrile patients often become fatigued, antisocial, and exhibit other sickness-related behaviors. Specific brain areas are thought to control body temperature by triggering various mechanisms that produce or dissipate heat, but how thermoregulatory neurons modulate thermo-adaptive and other behaviors is unknown. I will use recently developed tools for genetic profiling and circuit analysis to molecularly identify thermoregulatory and fever-inducing neurons and map their connectivity patterns, thereby gaining new insight into thermoregulatory circuits and how they are connected to other homeostatic and social functions in the brain.
Department of Molecular Biology, Princeton University, Princeton, New JerseyRead more
Department of Molecular Biology, Princeton University, Princeton, New Jersey
Manipulating pseudomonas aeruginosa quorum-sensing to control pathogenicity, with Bonnie Bassler
Quorum sensing is a mechanism of cell-cell communication that allows bacteria to synchronously control processes that are only productive when undertaken in unison by the collective. I will focus on Pseudomonas aeruginosa because it has a well-defined quorum sensing network that is essential for biofilm formation and virulence factor production, and because P. aeruginosa is an important pathogen that affects cystic fibrosis sufferers, cancer patients undergoing chemotherapy, burn victims, and patients with implanted medical devices.
My work combines structural biology, chemistry, and genetics to define the mechanisms underlying activation and inhibition of quorum-sensing receptors with the aim of understanding how quorum sensing receptors accurately decode the information contained in small molecule signals to drive collective behaviors. These investigations could lead to strategies for controlling quorum sensing, potentially resulting in the development of anti-microbial drugs aimed at bacteria that use quorum sensing to control virulence and biofilm formation.
Department of Biology, Massachusetts Institute of Technology, Cambridge, MassachusettsRead more
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts
Role of splicing regulatory factors in co-regulated transcription and splicing, with Christopher Burge
My current research in Chris Burges lab focuses on using experimental and computational genomic approaches to understand coordinated shifts in gene regulation across cell types or changing cellular conditions focusing on interactions between transcriptional and post-transcriptional RNA regulatory processes. In particular, I am interested in better characterizing the mechanisms, factors, and genetic elements involved in co-regulating transcription and splicing differences in mammalian systems.
I grew up in Stamford, CT and was introduced to scientific discovery early on by my scientist parents. I received my undergraduate degree from the University of Pennsylvania, double majoring in biochemistry and anthropology. I was first immersed in genetic research while working in a molecular anthropology lab at Penn studying the genetic history of human migrations. Inspired by this experience, I went on to do my Ph.D. in human genetics with Yoav Gilad at the University of Chicago. My graduate research focused on two aspects of functional genomics: (1) using comparative genomic approaches to characterize regulatory patterns underlying gene expression differences across primate species and (2) mapping genetic variants that underlie changes in gene regulation and downstream gene expression within humans. Im hoping that my postdoctoral research will help me better understand the precise molecular mechanisms underlying regulatory differences between species, individuals, and tissues. Outside of lab, I enjoy experimenting with unique ingredients and cooking techniques, trying out new forms of exercise, and traveling.
Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University, New York, New YorkRead more
Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University, New York, New York
Molecular mechanism of chloride ion transport by CLC protein family, with Roderick MacKinnon
My current research focus is on understanding molecular mechanisms of CLC proteins, ubiquitous membrane proteins that transport chloride ions across membranes. The CLC proteins are involved in various biological processes including regulation of membrane potential, electrolyte/fluid transport across epithelia, and control of intravesicular pH. Mutations in CLC genes cause many hereditary disorders in humans. An interesting aspect of the CLC family is that a common structural architecture seems to be used for both active and passive ion transport. Some CLCs are chloride channels, which provide a passive pore for chloride ion conduction, whereas others function as secondary active transporters that exchange two chloride ions for one proton. Despite recent advances in our understanding of their mechanisms, fundamental questions remain unanswered, especially regarding how exactly CLC transporters couple the transfer of chloride and proton ions and what leads to the mechanistic difference between the channels and transporters. In the MacKinnon lab, I use structural and functional approaches to address these questions.
Department of Molecular and Cell Biology, University of California, BerkeleyRead more
Department of Molecular and Cell Biology, University of California, BerkeleySponsor: Michael Rape
Ubiquitin regulation of neural development and cell fate
The goal of my postdoctoral research is to discover essential regulatory mechanisms that control neural developmental programs and cell fates in a complex organism. Abnormal neural development is central to many pediatric diseases and the source of many cancers originating in the nervous system. Development requires precise signaling pathways to facilitate cell-cell communication and maintain normal function and prevent disease. Thus, I propose to study neural development in Xenopus tropicalis embryos, an established model system, and identify evolutionarily conserved complexes in human embryonic stem cells undergoing neuronal differentiation. A small modifying protein, ubiquitin is an important part of regulatory pathways that control nearly every aspect of cell physiology and is frequently perturbed in cancer. Recent work has demonstrated that ubiquitin modification is an essential regulator of development and cell fate. I will use combination of genetic, proteomic, biochemical, and cell biology techniques to identify crucial ubiquitin complexes and reveal the molecular mechanism of neural differentiation programs. Together, this work will provide unprecedented insight into the regulation of early embryonic differentiation programs and reveal therapeutic avenues to treat human cancers.
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CaliforniaRead more
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California
Engineering novel allosteric control over synthetic T cell receptors to improve cancer immunotherapy, with Wendell Lim
I am interested in both the general biochemical principles that govern cellular signaling and the development of synthetic biology approaches to control complex signaling networks and cellular behavior. These interests are complimentary as synthetic biology is often informed by knowledge obtained from studying natural cellular signaling mechanisms refined by evolution. In Wendell Lims lab at UCSF, I am using this two-pronged approach to engineer new receptors and signaling networks to control the activity and behavior of therapeutic T cells. Such engineered multi-layered regulation of cellular activity — an important characteristic of naturally occurring biological systems — has the potential to make cell-based therapeutics safer and more effective, a critical concern for this burgeoning therapeutic approach.
I grew up in Louisiana, moved to Texas for undergrad and received my Ph.D. in Immunology from the University of Texas Southwestern Medical Center at Dallas (UTSW) in January 2013. There I studied fundamental cellular and biochemical mechanisms that regulate T cell activation at the systems-scale in Christoph Wülfings lab. Before graduate school, I did a wide-range of research. One of my major contributions was in Colleen McClungs lab in the Department of Psychiatry and Neuroscience at UTSW where I characterized the first mouse model resembling human mania caused by disruption of the circadian rhythm transcription factor, Clock. Outside of lab, I enjoy biking, climbing, and exploring the San Francisco Bay Area.
Department of Biochemistry and Biophysics & Cellular and Molecular Pharmacology, University of California, San Francisco, CaliforniaRead more
Department of Biochemistry and Biophysics & Cellular and Molecular Pharmacology, University of California, San Francisco, California
Characterization of the endoplasmic reticulum membrane protein complex, with Adam Frost and Jonathan Weissman
Polytopic membrane proteins undergo a complicated folding process, whereby they must be co-translationally targeted to the endoplasmic reticulum (ER) for maturation and export to cellular membranes. While our understanding of the chaperones involved in soluble protein folding has rapidly expanded, there is little known about the chaperones dedicated to folding and quality control of membrane proteins. Recently, a conserved ER membrane protein complex (EMC) was discovered from a genetic screen in yeast aimed at identifying genes that disrupt the ER protein folding environment. Genetic interaction patterns arising from deletion of the EMC and preliminary biochemical data suggest the EMC may function as a chaperone for polytopic membrane proteins. As a postdoctoral fellow in the Frost and Weissman laboratories at UCSF, I plan to use a combination of approaches ranging from cryo-electron microscopy to genetics and cell biology to elucidate how the EMC affects membrane protein topology in yeast and human cells.
Division of Basic Sciences, Fred Hutchinson Cancer Research CenterRead more
Division of Basic Sciences, Fred Hutchinson Cancer Research CenterSponsor: Malik Harmit
Do genetic conflicts shape the actin cytoskeleton in eukaryotes?
I am interested in how evolution has shaped the eukaryotic actin cytoskeleton. The actin cytoskeleton is a critical force-generating polymer that powers fundamental cellular processes, including cell motility, vesicle transport and cytokinesis. Despite actins being among the most highly conserved proteins in eukaryotes, a number of actin variants and their regulators show strong signatures of genetic innovation in Drosophilids. Birth and death of novel actins have occurred between lineages and a few actin genes appear to rapidly evolve, suggestive of positive selection. Using genetic, evolutionary and cell biological analyses, I am investigating the evolutionary causes and functional consequences of genetic changes among components of the actin cytoskeleton with Drosophila melanogaster as the model organism. Exploring the actin cytoskeleton and its regulation from an evolutionary vantage will provide insight into the selective pressure on actins and how it is harnessed in many cellular processes.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical SchoolRead more
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School
Mechanism of incision-independent interstrand cross-link repair
Labratory of neurosciences and behavior, The Rockefeller UniversityRead more
Labratory of neurosciences and behavior, The Rockefeller UniversitySponsor: Leslie Voshall
Arousal and motivation in the female mosquito
Female mosquitos seek out hosts for blood meals, a behavior that is required for reproduction and that evolved several times in insect evolution. Host seeking is a persistent behavioral state composed of sequential behaviors such as taking flight, searching, landing, and feeding. It is not known how these behaviors are coordinated nor how this persistent motivational state is signaled in the brain.
I propose to study sequential host-seeking behaviors by applying an automated behavior classification system to track multiple mosquitoes in three dimensions as they seek out and feed on a human host. Because of the important role of dopamine in insect decision making, I will use genetic approaches to manipulate dopamine signaling circuits in the mosquito Aedes aegypti. I will assess the effect of these perturbations during host seeking and during an assay simulating host defensive behavior. These experiments will give a description of the role of dopamine signaling in a sustained complex behavior that evolved in the common ancestor of mosquitoes.
Department of Cell Biology, Harvard Medical SchoolSponsor: Stephen Liberles
Understanding gut-to-brain signaling through the vagus nerve
The vagus nerve is a key part of the neuroendocrine axis that controls feeding behavior and metabolism. Within the gastrointestinal tract, vagal sensory neurons detect ingested nutrients and mechanical stretch of the stomach, although underlying sensory transduction mechanisms are not understood. Basic questions remain about how ingested food is sensed, and how inputs are relayed centrally to coordinate systemic responses. Unraveling the functions of different vagal sensory neuron types in feeding behavior and metabolism control would provide a basic understanding of gut-to-brain communication mechanisms, and perhaps provide new therapeutic targets to control appetite and help treat metabolic disorders like diabetes, obesity and anorexia.
I am working towards characterizing a subpopulation of vagal sensory neurons that express cholecystokinin receptor type- A (CCKAR), a receptor for the gut satiety hormone cholecystokinin (CCK). Using transgenic mice, anatomical tract tracing, calcium imaging and optogenetics I want to understand the structure and function of the neural circuits formed by these sensory neurons. These studies will enable long-term efforts to shed light on the sensory biology of the vagus nerve- from understanding signal transduction mechanisms in the periphery to determining the organization of central inputs that orchestrate behavioral and endocrine responses.
Department of Biology, Massachusetts Institute of TechnologySponsor: Barbara Imperiali
Interrogating macromolecular interactions at biological membranes
I am passionate about biological processes that occur at cellular membranes. Membranes not only define the borders of cells but also create a fascinating physicochemical environment for a wide diversity of functions. The broad questions that I have been addressing focus on understanding the role of membrane lipids in the function of membrane peptides and membrane protein complexes and developing innovative methods for modulating lipid-peptide or lipid-protein interactions in order to control biological responses.
During my graduate research in France under the supervision of Prof. Solange Lavielle and Dr. Fabienne Burlina (at the École Normale Supérieure and the Pierre and Marie Curie University), I studied the spontaneous translocation of peptides through cell membranes that can be used as drug delivery agents. I characterized the translocation event at the molecular level, which provided pertinent clues to the design of drug delivery vectors with enhanced translocation abilities.
As a post-doctoral fellow in the laboratory of Prof. Barbara Imperiali (at Massachusetts Institute of Technology), my overarching goal is to decipher the organization and dynamics of supramolecular membrane protein complexes that are part of the N-linked protein glycosylation pathway of pathogenic bacteria. I propose to complement the current methods with an integrated strategy that will merge cell-free membrane protein expression, bioorthogonal labeling and membrane bilayer Nanodiscs. When combined, these technologies will give access to site-specifically labeled membrane-resident protein samples for detailed single-molecule biophysical analysis.
Department of Gastroenterology and Nutrition, Boston Childrens Hospital, Boston, MassachusettsRead more
Department of Gastroenterology and Nutrition, Boston Childrens Hospital, Boston, Massachusetts
Dissecting early host endotoxin sensing mechanisms, with Jonathan Kagan
My first contact with the field of host and pathogen interaction dated back to the time when I was working at Dr. Feng Shao’s Lab at the National Institute of Biological Sciences, Beijing (NIBS), one of the most prestigious research institute in China. My intern project was to clone and characterize the host substrates of an E3 ubiquitin ligase domain containing effector protein from the vacuolar pathogen Legionella pneumophila. From this experience, I was deeply impressed by the broad array of biochemical mechanisms employed by the bacterial effector proteins to manipulate host functions in order to survive and proliferate inside the host. Furthermore, this experience built up my passion and determination to launch my research journey in host and pathogen interaction.
A year later after my internship, I went on to pursuit my graduate study in Dr. Zhao-Qing Luos Lab at Purdue University. My research projects have been focused on the manipulation of host membrane trafficking pathways by Legionella effectors. Specifically, I have discovered that Legionella effector proteins exploited distinct post-translational modification mechanisms, i.e. reversible AMPylation and Phosphorylcholination, to regulate the activities of the host small GTPase Rab1. In summary, these findings highlight the sophisticated nature of host-pathogen interactions and reveals that bacterium has the ability to rewire host signaling events for its own benefit.
Living in the ocean of microorganisms, the innate immune system is the first line of defense to protect host from invading pathogens and to maintain tissue homeostasis. Thus, for my postdoctoral training, I would like to branch out my research focus from microbial pathogenesis into studying the cell biological and biochemical regulatory mechanisms of the host innate immune response. Particularly, I will decipher the spatial-temporal relationships among the earliest cell biological events triggered by endotoxin, such as receptor endocytosis, reactive oxygen production, LC3 associated phagocytosis and SMOC formation. I believe that my proposed research will provide new insights into the previously unexplored area of TLR signaling.
Department of Chemistry and Chemical Biology, Harvard UniversitySponsor: David Liu
Development of smart genome-editing agents for targeted therapy
Genetic abnormality is the root cause of many diseases. Canonical therapeutics primarily function by binding to the disease-associated proteins and modulating their activity. The recent advent of programmable sequence-specific endonucleases, however, has raised the possibility of direct manipulation of the corresponding genes and could eventually lead to effective cures of many diseases. The therapeutic potential of genome-editing agents is currently limited due to undesired DNA modifications including activity at off-target DNA sites and activity (on-target or off-target) in cells that are not the target population. My research focuses on developing genome-editing agents responsive to various endogenous and exogenous signals with improved specificity
Department of Molecular and Cell Biology, University of California, Berkeley, CaliforniaRead more
Department of Molecular and Cell Biology, University of California, Berkeley, California
Bookmarking the chromosomes and its role in cellular memory, with Robert Tjian
Cellular memory can be defined as the ability of a cell to transmit all its identifying functions to daughter cells during cell division. This ability to remember identity is crucial to the development of multicellular organisms, as evidenced when cells lose their identity and degenerate or become cancerous. Conversely, our ability to alter cell state, such as the generation of induced pluripotent stem (iPS) cells from differentiated cells, has become a promising therapeutic tool. Therefore, understanding how cells establish, maintain, and change identity will further our understanding of processes central to cellular development, disease progression, and therapy production. One mechanism for cellular memory is the ability to re-establish the transcriptional program following mitosis, which may function through bookmarking, the process of DNA-binding factors marking genes on condensed mitotic chromosomes to facilitate gene expression following mitosis. The main objective of this proposal is to analyze the mechanisms of bookmarking. I outline three independent approaches to characterize quantitatively the mechanisms of bookmarking. Using these approaches, I will test the hypothesis that histone variants and pluripotency factors function as bookmarkers to maintain the stem cell state. Lastly, I will perform an unbiased screen to identify putative bookmarking factors specific to embryonic stem cells.
Department of Molecular and Cellular Biology, Harvard University and Roberto Kolter, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MassachusettsRead more
Department of Molecular and Cellular Biology, Harvard University and Roberto Kolter, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts
Dissecting the molecular basis of mutually beneficial interactions between plants and bacteria, with Richard M. Losick
Many bacteria form complex multicellular communities known as biofilms. In these communities, cells are encased in a self-produced matrix that shield bacteria from diverse environmental stresses, antimicrobial agents, and host immune systems. Biofilms impact many arenas, including human health, ecology, and agriculture. Due to the importance and ubiquity of biofilms, there is increased interest in investigating the molecular mechanisms underlying the formation and maintenance of these communities. The soil bacterium Bacillus subtilis forms multicellular communities on the roots of some plants, including tomatoes, resulting in increased plant growth. My research examines how environmental signals are sensed by B. subtilis, initiating the biofilm program.
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New YorkRead more
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York
Functional and mechanistic study of histone crotonylation in leukemias, with C. David Allis
My research interest is to understand the epigenetic mechanisms that drive cancer development. With a focus on a few newly discovered histone posttranslational modifications, I am currently studying their functional roles and mechanisms in cellular differentiation and oncogenesis.
I spent my first 18 years in Hainan, a beautiful island located in the South China Sea before I moved to Beijing where I received B.S. degree in Biology from Tsinghua University. Initial exposure to scientific research at Tsinghua got me fascinated about science and promoted me to pursue graduate studies at Princeton University, where, in Dr. Yibin Kangs laboratory, I investigated the genetic causes underlying cancer initiation and metastasis. Appreciating that the interplay between genetic and epigenetic regulations is important in cancer development, I joined the laboratory of Dr. David Allis as a postdoc fellow where I continue studies in cancer research with a different focus on epigenetic causes of cancer. Outside of the lab, I enjoy the outdoors, spending time with family and friends, and trying delicious food.
Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MassachusettsRead more
Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts
Imaging protein translation at the single-molecule level in living cells, with Xiaowei Zhuang
Translation mediates the flow of genetic information encoded in mRNAs to proteins and can be regulated by many factors, contributing an essential part to the cellular gene expression regulation program. To understand how translation are influenced by various factors such as extracellular stimuli, cell metabolic states, subcellular localizations and so on, a method that could reveal the timing, location and level of translation activity on a defined single mRNA transcript in living cells would be invaluable. My research focuses on the development of a fluorescence imaging based method to study translation on a single mRNA transcript in living cells. I am going to use this method to study translation initiation and elongation under different conditions and at different subcellular compartments, such as neuronal dendrites and axons, to obtain previously unavailable information of translation dynamics.
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CaliforniaRead more
Mechanisms of mitotic spindle positioning by cortical dynein, with Ronald Vale
During mitosis, the position of the spindle determines the size, the relative orientation and the developmental fate of daughter cells. The spindle is positioned by a pulling force generated by cortically localized dynein and exerted on astral microtubules that are connected to the spindle poles. Dynein is anchored to the cell cortex by the protein NuMA and activated to pull on the end of microtubule, the mechanism of which remains unknown. To investigate this, we will first systematically define and characterize the interaction between NuMA and dynein using purified components. Next we will reconstitute the microtubule end capturing and pulling force generation activities of dynein using a microfabricated barrier based system, in which the regulation of dynein by NuMA will be investigated. In addition, we will determine the crystal structure of the complex of NuMA-dynein binding regions to reveal the structural basis for their interactions. Finally, the overall structure of full-length NuMA will be examined using electron microscope and the functional significance of NuMA oligomerization will be determined. Together our proposed study will provide a mechanistic understanding of how dynein is recruited and activated by NuMA to generate cortical pulling force for mitotic spindle positioning.
Department of Biology, Massachusetts Institute of Technology
Probing the role of peptidoglycan in establishing bacterial cell poloarity
Department of Molecular and Cell Biology, Physics and Chemistry, University of California, Berkeley, CaliforniaRead more
Department of Molecular and Cell Biology, Physics and Chemistry, University of California, Berkeley, California
RNA ribosome and RNA polymerase: Three molecules at a time, with Carlos Bustamante
Transcription by RNA Polymerase and translation by the Ribosome are two fundamental and important processes that shape cellular identity. Mutations that disrupt these processes can result in disease such as cancer. We strive to understand the underlying mechanisms of transcription and translation using optical tweezer. This single molecule technique allows us to monitor the actions of individual RNA Polymerase and the ribosome in real time that are often scored as averages in bulk measurements. We currently aim to scrutinize the activities of these molecular motors when coupled in the same reaction. The coupling between RNAP polymerase and the ribosome, which occurs in vivo in E. coli., constitutes an additional layer to control gene expression. A deeper understanding of both transcription and translation either alone or coupled will open up new ideas to curb or to cure diseases that stem from a malfunction in these process.
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts
Probing the molecular mechanism of ERAD-L, with Tom Rapaport
My research investigates the molecular mechanism of ER-associated degradation (ERAD). Using biochemical and structural tools, my study aims to understand how misfolded proteins in the ER are recognized, retro-translocated out of the ER into the cytosol, and subsequently degraded by proteasome.
I was born and grew up in one of the big city in China, Shanghai. After receiving BS in Biology from Fudan University, my strong interest in protein biochemistry brought me overseas to pursue my PhD in molecular biochemistry and biophysics from Yale University. Working in the lab of Karin M. Reinisch, my thesis work focused on solving structures of key regulators of membrane trafficking. Currently, I am doing postdoctoral work supervised by Tom Rapoport, in whose lab I learn new skills in the exciting field of membrane biology. Outside of the lab, I like painting, and enjoy life in Boston with my family and friends.
Laboratory of Neurogenetics and Behavior, The Rockefeller University, New York, New YorkRead more
Laboratory of Neurogenetics and Behavior, The Rockefeller University, New York, New York
Processing human cues in the mosquito brain, with Leslie Vosshall
Female mosquitoes require a blood-meal for reproduction, and show intense attraction to human hosts. They rely on host sensory cues, including carbon dioxide (CO2), and components of human body odor, such as lactic acid. These stimuli alone elicit little or no attraction, but in combination they synergize to trigger host-seeking behavior. After obtaining a blood-meal, female host-seeking behavior is switched off for several days. It is unknown where and how any human host cues such as, CO2 in breath, body odor, or body heat, are represented in the mosquito brain. It is also unknown how human host cues synergize to drive host attraction and ultimately trigger biting behavior, or how attraction is suppressed after a blood-meal. I will use two-photon excitation microscopy to measure activity in neural circuits in the mosquito brain to address these questions. This work will provide the first insights into how human cues are processed in the brain of the mosquito Aedes aegypti, which transmits Dengue Fever, Yellow Fever, and Chikungunya. The long-term aim of this research is to find novel approaches to intervene in mosquito biting behavior.
Department of Genetics, Brigham and Womens Hospital, Harvard Medical School, Boston, MassachusettsRead more
Department of Genetics, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts
Analysis of dosage compensation in Drosophila, with Mitzi Kuroda
I am interested in how binding of protein modifications contributes to the functions of chromatin complexes. Currently I am developing biochemical and proteomic methods to identify the histone modifications associated with malignant brain tumor (MBT) domain-containing proteins in human tissue culture cells and in fruit flies. The human and fly MBT-containing homologues participate in various aspects of Polycomb group silencing and tumor suppression. Since the MBT domain acts as a methyl lysine-binding module, it is likely that specific modification interactions together with protein interactions enable the localization of otherwise broadly pervasive MBT complexes to specific genomic regions. My graduate training in mass spectrometry complements my postdoctoral training in affinity pulldown of labile interactions with regard to uncovering these potential modification targets.
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New YorkRead more
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York
Functional segregation of taste-responsive neurons, with Charles Zuker and Tom Maniatis
I am studying the function of the mammalian taste system, in particular the molecular identity and diversity of taste-responsive neurons. The five basic taste qualities -sweet, sour, salty, bitter and umami, are detected on the tongue and palate epithelium by distinct classes of taste receptor cells (TRCs). The geniculate ganglion is the first neural station between the tongue and the brain; our lab recently showed that ganglion neurons are also tuned to specific taste qualities. My studies are aimed at understanding how TRC maintain the highly specific transfer of taste information between taste cells and the central nervous system, particularly given that TRCs turn over every few days. I have optimized a number of approaches to perform single-cell RNA sequencing both in TRCs and ganglion neurons, and am characterizing and classifying taste neurons into distinct classes. We hope to define molecular markers that will allow us to manipulate the connectivity, function and behavior of TRCs, and the taste system.
Department of Immunobiology, Yale University School of Medicine, New Haven, ConnecticutRead more
Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut
Counter-inflammatory mechanisms in tissue inflammation, with Ruslan Medzhitov
Many human diseases are associated with aberrant inflammation. While the inflammatory response functions to protect an organism against harmful pathogens or to restore tissue homeostasis, excessive inflammation is known to alter tissue functions and damage host tissues. This phenomenon is termed immunopathology and is a major contributor to human morbidity. Therefore, limiting immunopathology is critical in many pathological scenarios. There are two potential means to control immunopathology: to act on immune cells to directly suppress the generation of inflammatory response (anti-inflammatory mechanisms), or to act on target tissues to reduce or reverse the deleterious effects caused by inflammation (counter-inflammatory mechanisms). A body of previous works has contributed to our knowledge of the anti-inflammatory mechanisms, but the counter-inflammatory mechanisms remain largely elusive. Currently, I am using cellular responses to inflammatory cytokines as the experimental system to identify the counter-inflammatory signals. Meanwhile, I am characterizing their potential mechanisms by taking advantage of the computational and systematic approaches.
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MassachusettsRead more
Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts
Noxious chemical sensing by the TRPA1 ion channel, with Rachelle Gaudet
I am using structural techniques to study pain transduction by transient receptor potential (TRP) ion channels. TRPs comprise a large family of pain sensors activated by diverse stimuli from noxious temperatures to small molecules. My work focuses on understanding the regulation of ion channel opening by such stimuli at the atomic level.
My interest in biochemistry was piqued after taking organic chemistry as an undergraduate at UC Berkeley. I followed my interest in molecular detail to graduate school where I discovered my love for protein structure. During my PhD work at MIT, my studies of the enzyme ribonucleotide reductase led to a thesis focused entirely on allosteric regulation. Since then, I have been intrigued by how proteins use allostery to perform remarkable structural transformations that affect function. TRP channels are master integrators of allosteric signals. They are an ideal system for studying complex allostery and an atomic level understanding of TRP channel activation will provide a foundation for understanding pain.
Department of Microbiology and Immunology, University of California, San FranciscoRead more
Department of Microbiology and Immunology, University of California, San FranciscoSponsor: Alexander Johnson
Molecular analysis of bistability in a eukaryotic transcriptional network
Transcription circuits, defined as transcription regulators and the DNA cis-regulatory sequences they bind, control the expression of genes and define cellular identity. In eukaryotic cells, regulatory networks tend to be large, containing many highly interconnected transcription factors. Many of these complex networks are bistable, meaning they can toggle between two stable steady states. Bistable networks are responsible for such varied processes such as irreversible decisions during cell cycle progression, embryonic stem cell differentiation and oocyte maturation.
I study a bistable transcriptional network in the human commensal yeast Candida albicans that controls an epigenetic switch between two distinct cell types. This network shows many features of those in higher eukaryotes including the high degree of stability of each cell type. The goal of my research is to gain a molecular understanding of the functional differences between the multiple feedback loops present in bistable transcriptional circuits. This analysis will serve as a model for the general understanding of complex circuits.
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MarylandRead more
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
Acetylomics of the leukemia protein MOZ, with Philip Cole
Once thought to be limited to histones, protein acetylation has now expanded to include a plethora of other protein substrates. I am utilizing human protein microarrays to identify novel targets of the lysine acetyltransferases p300 and CBP, two commonly mutated proteins in hematological and other malignancies. Additionally we plan to identify the acetylation sites on these novel substrates by mass spectrometry, the cellular consequences of their acetylation, and the specific mechanisms of these effects using semi-synthetic protein constructs. Of high interest are substrates of which the acetylation is modulated by a small molecule bromodomain ligand. I am also characterizing the effect of this ligand on nucleosome acetylation. The importance of the bromodomain in regulating p300/CBP activity will be clarified by p300 bromodomain mutants.