Current Fellows

View as:
Jeanine Amacher

Department of Molecular and Cell Biology, University of California, Berkeley, California

Read more

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 Kuriyan’s 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 Cbl’s 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.

Michel Becuwe

Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts

Read more

Mechanisms of lipid droplet formation, with Robert Farese

Brittany Belin

Division of Biology: Geological & Planetary Sciences, California Institute of Technology, Pasadena, California

Read more

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.

Marco Bezzi

Department of Genetics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

Read more

The role of circular RNAs in prostate cancer development and progression, with Pier Paolo Pandolfi

Manasi Bhate

Department of Pharmaceutical Chemistry, University of California, San Francisco

Read more

Design of peptides to target protein-protein interfaces of membrane fusogens, with Willam DeGrado

I am broadly interested in the structure, function and dynamics of proteins that mediate signal transduction across the cellular membrane. These include membrane receptors, enzymes, ion channels and transporters. Since signaling is a dynamic process we need to study the ensemble of protein conformations and motions to understand how physical and chemical stimuli are converted into cellular information.

My graduate training was in solid-state NMR of membrane proteins. I currently use a combination of NMR, protein engineering and biophysics to gain quantitative insights into a family of transmembrane kinases that allow bacteria to sense and adapt to antibiotics in their environment.

Personal Website :

Kenneth Bohnert

Department of Biochemistry and Biophysics, University of California, San Francisco

Read more

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.

David Booth

Department of Molecular and Cellular Biology, University of California, Berkeley, California

Read more

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.

Margot Bowen

Radiation Oncology, Stanford University School of Medicine, Stanford, California

Read more

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.

Breann Brown

Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts

Read more

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.

Alejandro Burga- Ramos

Department of Human Genetics, University of California, Los Angeles

Read more

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.

Joseph Castellano

Department of Neurology and Neurological Sciences, Stanford University, Stanford, California

Read more

Effects of irradiation injury on systemic-neurogenic communication as targets for limiting cognitive dysfunction, with Tony Wyss-Coray

During my Ph.D. studies at Washington University, I worked with David Holtzman to show that ApoE e4 may increase Alzheimer’s disease risk by impairing Ab clearance from the brain, thus shifting the onset of its accumulation. My interest in neurodegeneration and aging motivated me to understand factors that regulate aging and brain health in unconventional ways. My project as a Jane Coffin Childs fellow in Tony Wyss-Coray’s laboratory has been to elucidate a novel systemic-neurogenic communication mechanism that appears to be disrupted in the context of brain irradiation therapy. Specifically, I am investigating the role of immune signaling molecules in mediating the neurogenic and cognitive dysfunction observed in the post-irradiation syndrome in pediatric brain cancer patients. Additionally, I am actively pursuing whether related blood-borne signaling molecules in young plasma may be sufficient to ameliorate age-related decreases in cognition and synaptic plasticity. To examine these complex mechanisms, I am leveraging various physiological methods, including plasma transfer and parabiosis.

Yi Chen

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts

Read more

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.

Feng Chen

Department of Surgery, University of California, San Francisco, California

Read more

Understanding liver bile duct formation to grow biliary tubes in vitro, with Holger Willenbring

Jia-Yun Chen

Department of Systems Biology, Harvard Medical School, Boston, Massachusetts

Read more

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 Lahav’s 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.

Gheorghe Chistol

Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts

Read more

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 sponsor’s 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.

Sandipan Chowdhury

Vollum Institute, Oregon Health and Science University, Portland Oregon

Read more

Structure of the NR1-NR2 subtype of the NMDA receptor in the open state, with Eric Gouaux

Edward Chuong

Department of Human Genetics, University of Utah, Salt Lake City, Utah

Read more

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.

Joseph Cotruvo

Department of Chemistry, University of California, Berkeley, California

Read more

Intersection of nitric-oxide and copper-mediated signaling pathways in mammalian cells, with Christopher Chang

Nitric oxide (NO) is a ubiquitous gasotransmitter involved in vasorelaxation, neurodegeneration, apoptosis, and other processes, and linked to numerous pathologies, including cancer. A major mechanism of NO signaling is S-nitrosation, the oxidative modification of cysteine residues, but how this occurs in vivo is poorly understood. Copper ions catalyze Snitrosation in vitro, while recent data point to mobile pools of copper playing unknown roles in signaling pathways. This proposal aims to connect copper- and NO-mediated signaling, using the lipolysis pathway of adipocytes as a model system. Our preliminary data suggest copper and NO modulate the activity of phosphodiesterase (PDE) 3B. We propose that copper, bound to a protein or small molecule, catalyzes S-nitrosation of PDE3B, inhibiting the enzyme. We will test this hypothesis by altering cellular copper and NO levels via gene knockdowns, and assaying PDE3B activity in extracts. We will detect differences in PDE3B S-nitrosation under these conditions and determine the cysteine(s) modified. Finally, we will search for endogenous copper ligands and reconstitute the S-nitrosation system in vitro. These studies will yield insights into NO’s physiology, unravel a novel signaling role of copper, and motivate examination of copper signaling in other mammalian cell types.

Lei Dai

Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California

Read more

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.

Morgan DeSantis

Department of Cellular and Molecular Medicine, University of California, San Diego

Read more

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.

Ines Drinnenberg

Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington

Read more

Causes and consequences of a non-canonical H2A variant in flies, with Harmit Malik

My research focuses on the evolutionary diversity of centromeric architectures. Faithful chromosome segregation in all eukaryotes relies on centromeres, the chromosomal sites that recruit the kinetochore protein complex to mediate spindle attachment during cell division. Yet, despite this essential function centromeres are remarkably diverse. Most chromosomes are monocentric i.e., kinetochore assembly is restricted to a defined chromosomal region. In contrast, holocentromeres have kinetochores attached along the entire length of chromosomes. Holocentric chromosomes have evolved multiple times independently from monocentric ancestors. Yet, despite their dramatically different centromeric architectures, the transition to holocentric chromosomes has remained enigmatic.

I performed a computational survey for centromere and kinetochore components in mono- and holocentric insect orders. This study revealed the unexpected finding that the centromere specific histone variant, CenH3 – known to be essential for centromere function in most eukaryotes – was lost on all four lineages that are associated with independent transitions from mono- to holocentric chromosomes. Expanding my analyses to other kinetochore components I found that homologs of many inner kinetochore proteins are still present, suggesting that holocentric insects utilize alternative ways of initiating kinetochore assembly on chromatin. Currently I am in the process of determining the CenH3-independent kinetochore assembly pathway as well as the molecular architecture of the insect holocentromere.

Dina Faddah

Department of Physiology, University of California, San Francisco, California

Read more

Genetic identification of a neural circuit that controls salt appetite, with Zachary Knight and Nirao Shah

Jeffrey Farrell

Department of Molecular and Cellular Biology, Harvard University, Boston, Massachusetts

Read more

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.

Laura Gaydos

Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington

Read more

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.

Jose Gomez

Department of Pathology & Developmental Biology, Stanford University School of Medicine, Stanford, California

Read more

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.

Adam Granger

Department of Neurobiology, Harvard Medical School, Boston, Massachusetts

Read more

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.

Ethan Greenblatt

Department of Embryology, Carnegie Institution of Washington, Baltimore, Maryland

Read more

Understanding the nuclear aging in the Drosophila follicle stem lineage, with Allan Spradling

Aging is characterized by a progressive decline in tissue physiology. The reasons for this decline, whether antagonistic pleiotropy, error catastrophe, or developmental programming, have been difficult to pinpoint. Likewise, which cell types and subcellular components are the most important targets of decline remain hotly debated. I have long been interested in aging despite its acknowledged difficulty as a research topic. The submitted proposal describes my strategy for testing ideas and approaches that I believe have the potential to greatly advance this field, and to launch my career as an independent investigator. My approach involves a novel system in which to study aging – the Drosophila follicle stem cell lineage, and a novel hypothesis regarding a primary target of the aging process – the epigenetic system of the cell nucleus.

Joshua Gruber

Department of Genetics, Stanford University, Stanford, California

Read more

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.

Shawna Guillemette

Department of Genetics, Brigham and Women’s Hospital, Boston, Massachusetts

Read more

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 Vigoreaux’s lab where I investigated mechanisms of energy transport in Drosophila flight muscle. As a graduate student in Sharon Cantor’s 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.

Monica Guo

Department of Biology Massachusetts Institute of Technology, Cambridge, Massachusetts

Read more

Quantitative dissection of how genome organization impacts gene expression with Michael Laub

Christine Hagan

Department of Systems Biology, Harvard Medical School, Boston, Massachusetts

Read more

Biochemical studies of the membrane-associated steps in the Wnt signaling pathway, with Marc Kirschner

Signaling between cells through the Wnt pathway critically affects cell fates during embryonic development and in disease states, such as cancer. Many of the components of the Wnt pathway have been identified, and it is known that activation of the pathway ultimately leads to the cytoplasmic accumulation of beta-catenin, which then promotes transcription of a set of target genes. However, the molecular mechanism of signal transduction that leads to the increase in beta-catenin is not clear. I propose to identify the specific roles of the upstream components of the pathway in regulating its activity by determining the sequence of protein recruitment, phosphorylation, and oligomerization events that occur on the Wnt membrane receptors in vivo by immunoprecipitation and blue native gel assays. This part of the pathway will then be reconstituted in vitro with purified membrane receptors and cell extracts so that the individual protein binding and phosphorylation steps can be separated by removing or mutating components, and their effect on beta-catenin degradation can be directly assessed. These experiments will thereby elucidate how the different proteins contribute to initiating or modulating the Wnt signal and may identify ways of interfering with the pathway that would be therapeutically useful.

Tina Han

Department of Physiology, University of California, San Francisco, California

Read more

Dynamics of RNA granule assembly in temperature synchronization of clock rhythms, with Lily Jan

I study the role played by TMEM16F, a phospholipid scramblase, in the generation of extracellular vesicles. TMEM16F is a transmembrane protein found in a family of calcium-activated chloride channels (CACCs). Mutations in TMEM16F cause a rare bleeding disorder called Scott Syndrome in which patients are deficient in platelet coagulant activity. Interestingly, 16F and four other members in this family have been implicated as phospholipid scramblases by disrupting plasma membrane asymmetry upon calcium activation. This is presumed to be a prerequisite step in the generation of extracellular vesicles, which are believed to deliver RNA and protein cargo as a form of cell-to-cell communication. It is also unclear whether TMEM16 proteins are themselves scramblases or how the protein might achieve bilateral phospholipid transport.

Angelika Harbauer

F.M. Kirby Neurobiology Center, Children’s Hospital Boston, Boston, Massachusetts

Read more

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 Parkinson’s 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 Parkinson’s disease.

Norbert Hill

Department of Molecular and Cell Biology, University of California, Berkeley, California

Read more

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.

Wei-Hsiang Huang

Department of Biology, Stanford University, Stanford, California

Read more

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.

Alex Hughes

Department of Pharmaceutical Chemistry, University of California, San Francisco, California

Read more

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.

Ruei-Jiun Hung

Department of Genetics, Harvard University, Boston, Massachusetts

Read more

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.

Alyssa Johnson

Department of Biochemistry & Biophysics, University of California, San Francisco, California

Read more

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, Alzheimer’s and Parkinson’s 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.

Duncan Leitch

Department of Physiology, University of California, San Francisco, California

Read more

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.

Manuel Leonetti

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California

Read more

Understanding sphingolipid homeostasis in human cells: function and regulation of ORMDL proteins, with Jonathan Weissman

Sphingolipids are essential membrane components and signaling messengers central to many cellular processes, in particular apoptosis. Consequently, sphingolipid levels are dysregulated in many diseases, in particular cancer. However, how cells sense and regulate their sphingolipid content is still poorly understood. The ORM membrane protein family, conserved from yeast to humans, is a key sphingolipid homeostatic sensor: the Weissman laboratory established that ORM proteins mediate a feedback response between cellular needs and de novo sphingolipid biosynthesis. While the molecular details of this response have been elucidated in yeast, how sphingolipids regulate the function of the mammalian orthologs (ORMDL) is completely unresolved. I propose to use a combination of biochemical and cellular biological approaches, together with a transformative genetic interaction mapping strategy, to characterize the mechanisms linking ORMDL function to sphingolipid homeostasis in human cells. Combining the expertise of our laboratory with my own background in membrane protein biochemistry, I will elucidate how the functional properties of ORMDL are modified by specific sphingolipid species and how ORMDL activity in turn modulates sphingolipid biosynthesis. My results will give substantial insights into the mechanism of sphingolipid homeostasis in humans and could open the way for new strategies for the therapeutic tuning of sphingolipid metabolism.

Wanhe Li

Laboratory of Genetics, The Rockefeller University, New York, New York

Read more

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.

Brian Liau

Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts

Read more

Activity-based profiling of lysine-specific demethylase 1, with Bradley Bernstein

My research interests lie at the interface of chemical biology with cancer epigenetics and chromatin biology. In Brad Bernstein’s lab, I am currently studying the function of histone demethylases in epigenetic-mediated mechanisms of drug persistence in glioma stem cells. We found that a subpopulation of glioma stem cells indefinitely persist in the presence of potent receptor tyrosine kinase inhibition by entering a slow-cycling state that recapitulates transcriptional and epigenetic features found in primary tumors. In particular, this slow-cycling state is characterized by high histone demethylase expression and widespread chromatin remodeling. We hypothesize that these demethylases may serve as key enablers of epigenetic plasticity in quiescent glioblastoma cells through the removal of chromatin barriers, thus catalyzing the transition to new epigenetic states that promote adaptation, survival, and disease recurrence. We hope to uncover the functions of histone demethylases in glioma and address the potential of attendant therapeutic strategies in neuro-oncology.

Anthony Lien

Gladstone Institute of Neurological Disease, The J. David Gladstone Institutes, University of California, San Francisco, California

Read more

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.

Siqi Liu

Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, New York

Read more

Exploring the mechanism of skin stem cell regulation in skin wound repair, with Elaine Fuchs

Xing Liu

Division of Biology, California Institute of Technology, Pasadena, California

Read more

Regulation of cullin-RING ubiquitin ligases by Cand1, with Raymond Deshaies

Protein function and stability can be modulated by attachment of ubiquitin, which is achieved by three sequentiallyoperating enzymes, of which the last enzyme in the cascade, ubiquitin ligase (E3), confers substrate recognition and ubiquitination. The Skp1–Cul1–F-box (SCF) complex is one type of cullin–RING ubiquitin ligase (CRL), and its substrate specificity is determined by which one of the 69 different F-box–Skp1 substrate adaptors is recruited to the Cul1 scaffold. Cul1 also binds Cand1 in a manner that is mutually exclusive with F-box–Skp1. Current studies have revealed that Cand1 is a novel exchange factor that equilibrates Cul1 with the total cellular pool of free F-box–Skp1 complexes. However, the mechanism and regulation of the Cand1-mediated protein exchange process and the impact of Cand1 on the cellular ubiquitinated proteome remain elusive. This proposal aims to provide insights into the mechanism and significance of Cand1 function through 1) analyzing Cand1-SCF interactions and effects of substrates at millisecond timescales, 2) investigating effects of Cand1 on Cul1 modifications, 3) evaluating changes in CRL assembly and activity in Cand1-depleted cells. These studies will deepen understanding of the biological role of Cand1 and how the repertoire of CRLs is sustained and regulated.

Wan-Lin Lo

Department of Medicine and Rheumatology, University of California, San Francisco, California

Read more

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.

Dan Ma

Department of Biological Structure, University of Washington, Seattle, Washington

Read more

Structural study of porcupine, a membrane protein essential to Wnt function, with Wenqing Xu

I’m 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.

I’m from China, and I got my PhD degree at Tsinghua University.  I used to be a structural biologist, and now I’m 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 I’m working as a postdoc in Seattle, a beautiful and romantic city, and I think I will enjoy my research and enjoy my life!

John Maciejowski

Laboratory of Cell Biology & Genetics, The Rockefeller University, New York, New York

Read more

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.

Nadja Makki

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco

Read more

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 Luo’s lab at Stanford to study the connectivity of individual neurons in the brain. For my current postdoc in Dr. Nadav Ahituv’s 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.

Satoru Miura

Department of Neurosciences, University of California, San Diego

Read more

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 animal’s 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.

Joshua Modell

Laboratory of Bacteriology, The Rockefeller University, New York, New York

Read more

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.

Erica Moehle

Department of Molecular and Cell Biology, University of California, Berkeley, California

Read more

Intra and trans-cellular mitochondrial communication in Parkinson’s 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 Guthrie’s laboratory. There, I studied how pre-mRNA splicing is regulated – in particular, how the cell coordinates a pre-mRNA’s transcription and its splicing. My interest in how discrete molecular processes are integrated inside the cell continues during my postdoctoral fellowship in Andrew Dillin’s 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.

Jeffrey Moore

Department of Molecular and Cell Biology, Harvard University, Cambridge, Massachusetts

Read more

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.

Sabin Mulepati

Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts

Read more

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 Bailey’s 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.

Eugene Oh

Department of Molecular and Cell Biology, University of California, Berkeley, California

Read more

Investigating the ubiquitin-dependent mechanisms that govern human stem cell maintenance and the course of neurogenesis, with Michael Rape

Ubiquitylation is a versatile post-translational modification required for most cell fate decisions. During neurogenesis, ubiquitin-dependent mechanisms ensure the irreversible transformation of neural stem cells into neurons. By contrast, the misregulation of the ubiquitylation system can set off a wide range of developmental abnormalities, from uncontrolled cell proliferation and tumor formation to neurodegeneration and cell death. Despite its medical relevance, our understanding of how ubiquitylation governs the course of human neurogenesis is far from complete. For my research fellowship, I propose to develop a large-scale screening platform to identify the ubiquitylating enzymes that promote the maintenance of undifferentiated human stem cells as well as those that facilitate the specification of neural cell fates. To better grasp the physiological parameters that underlie the directionality of cellular differentiation, I will define the collection of endogenous substrate proteins modified by the newly identified enzymes. Aside from generating a list of substrates, I aim to study the functional consequences of ubiquitylation by characterizing substrate mutants that are resistant to ubiquitylation in stem cells. Together, my results will shed light on fundamental principles of human development and potential mechanisms that cause neuronal cancers and neurodegenerative disorders.

Jon Paczkowski

Department of Molecular Biology, Princeton University, Princeton, New Jersey

Read more

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.

Athma Pai

Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts

Read more

Role of splicing regulatory factors in co-regulated transcription and splicing, with Christopher Burge

My current research in Chris Burge’s 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. I’m 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.

Eunyong Park

Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University, New York, New York

Read more

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.

Jessica Polka

Department of Systems Biology, Harvard Medical School, Boston, Massachusetts

Read more

Mobility and maintenance of a carbon-fixing micro compartment: bioengineering applications and insights into broad mechanisms of bacterial spatial organization, with Pamela A. Silver and Timothy J. Mitchison

I am interested in the mechanisms that guide proteins to assemble into mesoscale structures, from force-generating cytoskeletal polymers to metabolic microcompartments. While the basic principles underlying these systems underpin much of biological organization, I focus on tractable polymers found in bacteria. For example, as a graduate student in Dyche Mullins’ lab at UCSF, I reconstituted a three-component bacterial plasmid-segregating actin system in vitro and elucidated the multiple regulatory functions of its single accessory protein. As a postdoc, I have investigated the assembly of the carboxysome, a protein organelle in cyanobacteria that we found grows like a crystal until it is rapidly coated by a layer of shell proteins. Currently, I am interested in a long-range protrusive apparatus actuated by chemical changes.

I hope that a thorough understanding of these machines can permit the rational design of self-assembling structures suited for use in nanotechnology, metabolic engineering, and drug delivery.

Jeffrey Rasmussen

Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, California

Read more

Interactions between sensory neurons and skin, with Alvaro Sagasti

My work in Alvaro Sagasti’s lab focuses on interactions between the epidermis and the axons of touch-sensing neurons. I am particularly interested in how the epidermis regulates axon repair following injury.

I grew up in Ithaca, NY and received my BS in Computational Biology from Brown University. During my graduate studies at University of Washington in Seattle, WA, I became interested in the remarkable and diverse behaviors of epithelial cells. For my thesis, I studied mechanisms of epithelial tube formation in C. elegans with Jim Priess at the Fred Hutchinson Cancer Research Center. The Priess lab was a great place to learn genetics and cell biology and I am currently applying this training to understand how our largest epithelial organ – the skin – regulates repair of the sensory nervous system. Outside of the lab, my wife and I enjoy exploring Los Angeles with our son.

Kole Roybal

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California

Read more

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 Lim’s 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 Wülfing’s lab. Before graduate school, I did a wide-range of research. One of my major contributions was in Colleen McClung’s 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.

Nicole Schirle

Department of Biochemistry and Biophysics & Cellular and Molecular Pharmacology, University of California, San Francisco, California

Read more

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.

Elenoe Smith

Department of Hematology and Oncology, Boston Children’s Hospital, Boston, Massachusetts

Read more

DNA elements within BCL11A and its target sequences in globin switching, with Stuart Orkin

This project aims to identify cellular mechanisms contributing to elevation of fetal hemoglobin (HbF, ?2?2) levels, the most promising therapy for patients with sickle cell disease. The characterization of BCL11A, a repressor of HbF production, and potential BCL11A targets within the ?-globin locus, will impact therapy design and treatment of the major hemoglobin disorders whose global health burden is rising. Although BCL11A is dispensable for normal red cell function, studies in mice have determined that it is required for development, presenting a potential obstacle for therapies designed to inhibit BCL11A function by small molecule. Aim1 will determine the dependence of BCL11A erythroid expression on a single nucleotide polymorphism dense region, identified by genome wide association studies. Aim2 will identify a region required for ?-globin gene repression within the A?-? intergenic region of the ?-globin locus. Both aims will utilize DNA targeting of mouse embryonic stem cells and analysis of BCL11A expression and/or globin gene expression in fetal and adult mice. These studies will contribute to a fuller understanding of ?-globin gene regulation, provide in vivo models for molecular characterization of hemoglobin switching, and identify erythroid specific targets for therapeutic intervention.

Emerson Stewart

Department of Biology, Stanford University, Stanford, California

Read more

Molecular Mechanisms of presynaptic assembly and maintenance in C. elegans neurons, with Kang Shen

The human brain is a highly ordered structure, consisting of billions of neurons linked through trillions of intercellular connections. Among the most powerful computational machines known to man, the human brain controls everything from our ability to perceive the world around us to higher order functions involved in learning and memory. At the heart of the brain’s processing power lies the synapse.

Synapses are specialized subcellular structures that mediate communication between neurons, thereby dictating information flow within the nervous system. Numerous proteins involved in synapse formation have been identified, yet how active zone and synaptic vesicle proteins coalesce into highly ordered macromolecular complexes remains a fundamental question in neurobiology. I am interested in elucidating the molecular underpinnings that support synapse formation and maintenance.

To this end I will use the Hermaphrodite Specific Neuron in C. elegans to examine how synapses are formed during development and maintained throughout the lifespan of the organism. Through a combinatorial approach employing RNAi and forward genetic screens as well as fluorescent microscopy I will take advantage of the inherent benefits of the C. elegans system to study conserved processes of synapse formation in the context of an intact organism.

Bethany Strunk

Department of Cell and Developmental Biology, Life Sciences Institute, University of Michigan, Ann Arbor, Michigan

Read more

Elucidating mechanistic defects associated with dysregulation of a phosphatidylinositol signaling lipid, with Lois Weisman

Mutations in Fig4 cause the incurable neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and CharcotMarie-Tooth Syndrome (CMT) through dysregulation of phosphatidylinositol (3,5)-bisphosphate (PI3,5P2). A molecular understanding of the mechanisms by which Fig4 regulates both the transient production and rapid turnover of this signaling lipid will be essential for devising therapies. Fig4 is the lipid phosphatase responsible for dephosphorylating PI3,5P2 at the 5 position to produce phosphatidylinositol 3-phosphate (PI3P). Paradoxically, conserved residues in the yeast Fig4 phosphatase active site are required to activate the lipid kinase catalyzing the addition of the very phosphate it hydrolyses. This suggests an internal mechanism for preventing uncontrolled elevation of PI3,5P2 in the absence of the activity required to restore it to basal levels. The research proposed here will use a yeast model to elucidate the conserved mechanisms by which Fig4 controls both the synthesis and turnover of PI3,5P2 and uncover which of these mechanisms are disrupted by disease related mutations.

Yunhao Tan

Department of Gastroenterology and Nutrition, Boston Children’s Hospital, Boston, Massachusetts

Read more

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 Luo’s 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.

Sheila Teves

Department of Molecular and Cell Biology, University of California, Berkeley, California

Read more

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.

Sarah Wacker

Department of Molecular and Cellular Biology, Harvard University and Roberto Kolter, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts

Read more

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.

Liling Wan

Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York

Read more

Functional and mechanistic study of histone crotonylation in leukemia’s, 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 Kang’s 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.

Chong Wang

Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts

Read more

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.

Yuxiao Wang

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California

Read 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.

Liang Wee

Department of Molecular and Cell Biology, Physics and Chemistry, University of California, Berkeley, California

Read more

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.

Christina Woo

Department of Chemistry, Stanford University, California

Read more

Development of an isotopic labeling approach for rapid profiling of the O-glycoproteome, with Carolyn Bertozzi

My research involves using isotopic labeling strategies and computational methods to enable a novel chemical glycoproteomics platform termed Isotope Targeted Glycoproteomics (IsoTaG).  Given the strong correlation of altered glycosylation patterns with malignancy, glycosylated proteins may be an information-rich subset of the proteome from which cancer biomarkers can be discovered. We employ metabolic labeling as a means to tag specific classes of glycoproteins for enrichment from human tissue samples and subsequent identification by mass spectrometry. A challenge in this endeavor is defining sites of glycosylation on peptide digests derived from such complex samples. To facilitate this effort, we invented a targeted strategy to enable the detection and identification of glycosylated peptides independent of the mass of the pendant glycan. Collectively, these tools allow us to quantitatively profile changes in protein glycosylation associated with human cancer progression and embryonic stem cell differentiation.

Xudong Wu

Department of Cell Biology, Harvard Medical School, Boston, Massachusetts

Read more

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.

Meg Younger

Laboratory of Neurogenetics and Behavior, The Rockefeller University, New York, New York

Read more

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.

Barry Zee

Department of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

Read more

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.

Jin Zhang

Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York

Read more

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.

Xu Zhou

Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut

Read more

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.

Christina Zimanyi

Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts

Read more

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.

Beth Zucconi

Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland

Read more

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.