Department of Genetics, Stanford UniversitySponsor: Karla Kirkegaard
Determining how diverse RNA viruses manipulate the autophagy pathway
Viruses make excellent tools for studying host pathways because they have evolved ways to subvert or co-opt those pathways. I’m interested in the autophagy pathway- a highly conserved means for the cell to recycle cellular material during times of stress by promoting vesicle formation and subsequent degradation of cytoplasmic contents. Autophagy is a fascinating and broad-reaching area of research where there is still little mechanistic knowledge, but appears to be involved in many different diseases including cancer, neurodegenerative diseases, and infectious diseases.
I’m particularly interested in how viruses co-opt this pathway to promote their own replication and spread. To address the mechanisms by which viruses induce and interact with the autophagy pathway, I am using poliovirus infection in HeLa cells that have several key autophagy genes knocked out by Crispr-Cas9. This will allow me to explore how the virus interfaces with the distinct complexes of the autophagy pathway and how the virus utilizes these for replication. Using viruses to study this underlying cellular process may help uncover potential drug targets for other diseases where autophagy is implicated.
Department of Cellular and Molecular Pharmacology, University of California San FranciscoRead more
Department of Cellular and Molecular Pharmacology, University of California San FranciscoSponsor: Wendell Lim
Synthetic control of immune cell traffiking
Department of Biological Engineering, California Institute of TechnologyRead more
Department of Biological Engineering, California Institute of TechnologySponsor: Michael Elowitz
Dynamics of cell state transitions in early mammalian development
Synthetic recording of cell state trajectories during development
The incredible journey from a zygote to an animal entails transition of cells from one state to another as they proliferate. Although fundamental to our understanding of development, the trajectories of single cells during these transitions have been elusive due to technical limitations. A growing body of evidence suggests that cellular heterogeneity is prevalent in biological systems. Therefore, the average behavior of cell populations cannot be reliably used to infer the trajectories of the cells they comprise. Cellular behaviors are also highly dynamic. Techniques that rely only on static snapshots lose critical information about the longitudinal dynamics and spatial context of cells.
I am interested in developing methods for recording lineage and transcriptional event histories within the genome of the cells. Recently, our group has published a CRISPR/Cas9-based method, called MEMOIR, which involves “writing” of structured mutations at defined sites in the genome, where they can be read out using multiplexed in situ hybridization. Approaches analogous to phylogenetic inference can then be used to reconstruct lineage and event histories based on the mutation patterns. I seek to improve this system and implement it in mouse embryos to study dynamics of cell state transitions in early mammalian development. This work will provide the tools and theoretical basis for reconstructing lineage trees and decorating them with dynamic gene expression information, in virtually any developmental context.
Department of Physiology, University of California San FranciscoSponsor: Zachary Knight
Identification of homeostatic signals that regulate AgRP "hunger" neurons
Department of Molecular Biology and Princeton Neuroscience Institute, Princeton UniversityRead more
Department of Molecular Biology and Princeton Neuroscience Institute, Princeton University
Auditory coding contributing to drosophila courtship behavior
Department of Neurological Sciences, Stanford UniversitySponsor: Thomas Rando
A comparative genomic analysis of lifespan evolution in verterbrates
Aging can be viewed as the time-dependent decline in organismal function which increases the likelihood of death. How and why we age remains one of the greatest mysteries in modern biology. Interestingly, the rate of aging–and ultimately lifespan of organisms–varies greatly even within vertebrates. Among extant vertebrates, extreme longevity appears to have arisen multiple times independently, suggestive of convergent evolution. My project aims to uncover the genes and pathways that contribute to lifespan variation using comparative genomics. At present over 100 vertebrate genomes have been sequenced and are publically available. Included among these organisms are species with both remarkably short and long lifespans. I have set out to develop a computational pipeline which identifies regions that exhibit molecular convergence within the genome of species sharing a similar lifespan. I then plan to characterize these regions biochemically to determine their effects on expression, regulation, and function of the involved genes. Longer term, I will develop mutant mice harboring variants with significant effects on function to directly assess their influence on lifespan in a well-studied model of vertebrate aging.
Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MassachusettsRead more
Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
Mechanisms of lipid droplet formation, with Robert Farese
Stowers Institute for Medical ResearchSponsor: Alejandro Sanchez-Alvarado
Cell fate and intercellular signaling in planarian regenerative organizers
The growth and regeneration of adult tissues requires the establishment of local signals that regulate growth and differentiation. While signaling molecules regulating proliferation have been studied in a wide range of tissue and disease contexts, mechanisms linking tissue composition and cellular cooperativity to growth and regenerative potential are poorly understood. During development, signaling centers with a defined genetic signature – organizers – induce the proliferation, migration, and differentiation of neighboring cells and establish patterns critical for the formation of adult organ systems. However, it is unclear if comparable signaling centers regulate tumor development or regeneration. The planarian worm provides a unique opportunity to study the establishment and function of regenerative signaling centers in vivo due to its extraordinary ability to regenerate organ systems from tiny fragments in approximately one week.
As a postdoctoral fellow in the Sanchéz laboratory at the Stowers Institute for Medical Research, I plan to use a combination of sequencing and quantitative imaging techniques to identify the minimal cell types and tissue structures required for complete regeneration and accurate scaling of planarian worms. This work is expected to reveal novel mechanisms regulating self-organization and growth in resource-limited adult tissues and may expand our ability to improve human regenerative capacity and treat human cancers that arise from aging tissues.
Department of Molecular and Cellular Biology, University of California, Berkeley, CaliforniaRead more
Department of Molecular and Cellular Biology, University of California, Berkeley, California
Genetic regulation of multicellularity in a close relative to metazoans
The evolution of regulatory mechanisms to coordinate multicellular development was critical to the origin of animals. Fundamental mechanisms that led to animal multicellularity may also be conserved in the closest living relative of animals, the choanoflagellates, since one species, Salpingoeca rosetta, can transition to a multicellular form called a rosette in a process that is reminiscent of early embryogenesis in animals. To uncover how this multicellular transition is controlled in S. rosetta, we are establishing transgenic and genomic methods that will enable investigating how genes coordinate rosette development. These advances will provide essential tools for exploring the molecular biology of these ecologically and evolutionarily important organisms and potentially illuminate the earliest stages of animal evolution and development.
Radiation Oncology, Stanford University School of Medicine, Stanford, CaliforniaRead more
Radiation Oncology, Stanford University School of Medicine, Stanford, California
Consequences of p53 activation during development, with Laura Attardi
The p53 protein is a transcription factor that becomes activated in response to various cellular stress cues. Once activated, p53 induces target genes involved in apoptosis, cell cycle arrest, senescence and differentiation. Maintaining the correct levels of p53 is critical, since loss of p53 promotes cancer, while increased p53 activity promotes developmental defects and premature aging. To further define the consequences of increased p53 activity, the Attardi lab created a novel mouse model in which p53 is activated during embryogenesis. Intriguingly, this led to a variety of craniofacial and cardiovascular defects. This unique constellation of phenotypes is reminiscent of human CHARGE syndrome, which is caused by mutations in CHD7. I am now using our p53 mouse models to study the cellular and molecular mechanisms by which p53 promotes features of CHARGE syndrome. These studies will further our understanding of p53 as a mediator of developmental disease in addition to its role as a tumor suppressor.
Department of Medicine, Brigham and Women's HospitalSponsor: Stephen J Elledge
The role of ZNF292 in senescence and tumorigenesis
Senescence is an irreversible cell state characterized by permanent exit from the cell cycle that occurs in response to cellular stresses such as shortened telomeres and DNA damage. Thus, senescent cells accumulate as an organism ages and are thought to contribute to the gradual decline in tissue function as we age. Importantly, elimination of senescent cells in old mice extends healthy lifespan. Therefore, achieving a better understanding of the genetic underpinnings of senescence can lead to improved prevention and treatment of aging-related diseases.
It is currently thought that senescence is mediated by three distinct pathways, characterized by their primary facilitators: p53, p16 and GATA4. However, there are likely many more factors that are critical to senescence induction. Thus, we conducted a whole genome CRISPR screen for genes necessary for replicative senescence in IMR90 primary fibroblasts. One novel gene identified was ZNF292. Thus, the objective of my postdoctoral work is to gain a more thorough understanding of the role of ZNF292 in senescence and tumorigenesis.
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of TechnologyRead more
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Investigating mechanisms of immune evasion in autochthonous lung tumors
Helen Diller Family Comprehensive Cancer Center, University of California, San FranciscoRead more
Helen Diller Family Comprehensive Cancer Center, University of California, San FranciscoSponsor: Frank McCormick
Novel effectors of oncogenic KRAS that regulate cell signaling
RAS proteins are small GTPases that act as GDP/GTP-regulated switches and play an essential role in signal transduction, proliferation, and survival. Activating mutations in the different RAS isoforms (KRAS, HRAS, and NRAS) are found in several human pathologies, including cancer and developmental syndromes, such as Noonan and cardio-facio-cutaneous syndromes. Efforts in the field of chemistry have been made in order to target these oncogenic GTPases and recent discoveries have provided the first compounds capable to target KRAS directly. Using these chemical probes, mass spectrometry, and additional genetic strategies, I study the role of novel downstream effectors of activated GTP-bound RAS oncoproteins.
Identification of such molecular effectors will shed light into the mechanisms of pathogenesis of RAS oncoproteins and could also be used as an alternative way of therapeutically target the RAS pathway.
Department of Surgery, University of California, San Francisco, California
Understanding liver bile duct formation to grow biliary tubes in vitro, with Holger Willenbring
Department of Cellular and Molecular Pharmacology, University of California, San FranciscoRead more
Department of Cellular and Molecular Pharmacology, University of California, San FranciscoSponsor: Jonathan Weissman
Systemic analysis of the relationship between incRNAs and translation
Long non-coding RNAs (lncRNAs) have recently emerged as key functional molecules in gene regulation, with increasing evidence pointing to a role for lncRNAs in human diseases such as cancer. While the importance of a subset of nuclear lncRNAs in epigenetic and transcriptional gene regulation is well established, lncRNAs are also found in the cytoplasm and may function in different cytoplasmic processes including translational control. In particular, lncRNAs may regulate the translation of other transcripts; or, they may be associated with ribosomes and translated to produce short regulatory “micropeptides”. However, studying the roles for lncRNAs in translation has been hindered by the lack of high-throughput methods to systematically identify lncRNA candidates and probe how lncRNAs act globally to impact translation. Here, I propose a research program that uses a repertoire of genome-wide techniques, combining CRISPR interference and ribosome profiling, to provide fundamental insights into the novel role of lncRNAs in translational control.
Department of Biology, Stanford UniversitySponsor: Judith Frydman
Dissecting the protein folding mechanism by the TRiC chaperonin
Proteostasis is a central mechanism to regulate the health of the cellular proteome. Proteostasis dysfunction has been directly implicated in age-related diseases, including cancer. A central but very poorly understood component of proteostasis network is the eukaryotic chaperonin, TRiC/CCT. TRiC is an essential chaperone that assists folding and assembly of many proteins fundamentally important to cancer, including the tumor suppressors p53, VHL, telomerase as well as other cell cycle regulators. It is, therefore, not surprising that mis-regulation of TRiC is also linked to numerous pathological conditions. Indeed, several TRiC subunits are highly up-regulated in cancer, and their up-regulation is linked to poor prognosis. The paucity of structural and mechanistic knowledge on this complex has hindered the development of therapeutic strategies targeting TRiC. Therefore, my research in the Frydman lab focuses on closing this gap by defining the molecular basis of human TRiC to fold the key disease-linked proteins. I am interested in combining biochemical and structural methods to elucidate the underlying principles by which TRiC recognizes and folds proteins. I anticipate the result of this work will provide mechanistic insights relevant to human diseases.
Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller UniversityRead more
Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller UniversitySponsor: Roderick MacKinnon
Mechanisms of ATP-sensitive potassium, (KATP) channel gating
ATP-sensitive potassium channel (KATP) is an ion channel gated by ATP and ADP, and by doing so, it translates the metabolic state of a cell into electric signals. At molecular level, KATP is endowed with sensitivity to ATP and ADP through direct interactions with multiple binding sites. These binding sites are scattered across the entire KATP molecule, which is a tetramer of hetero-dimers that are composed of a type of inward rectifier potassium ion channel (Kir) and an ABC transporter (SUR).Previous studies have identified an inhibitory site on Kir that results in channel closure upon binding to ATP, and stimulatory sites on SUR that favor channel opening when occupied by either MgADP or MgATP. These observations pose a puzzle because in healthy cells ATP exists at millimolar concentrations whereas ADP is present only in the ten micromolar range. How then does KATP detect changes in ADP concentration when the background ATP concentration remains so high that ATP inhibition should dominate? To answer this question, we have to determine what the ATP and ADP affinities are at their respective sites and also understand how occupancy of these sites allosterically regulate the pore’s gate. Once this level of understanding is reached we can then try to predict the response of KATP to different metabolic states. Finally, we can integrate these responses into the broader signaling network that involves other closely related partners to describe the action of KATP at a systems biology level. My project in the MacKinnon lab aims to address this problem using a combination of electrophysiology and structural biology techniques.
Vollum Institute, Oregon Health and Science University, Portland OregonRead more
Vollum Institute, Oregon Health and Science University, Portland Oregon
Structure of the NR1-NR2 subtype of the NMDA receptor in the open state, with Eric Gouaux
Whithead Institute for Biomedical ResearchSponsor: Peter Reddien
The origin and evolution of cell types
Department of Biophysics and Biochemistry, University of California, San FranciscoRead more
Department of Biophysics and Biochemistry, University of California, San FranciscoSponsor: Hiten Madhani
Uncovering the molecular drivers of lethal invasive fungal infection
Department of Chemistry, Princeton UniversitySponsor: Tom Muir
Defining the interactome of the acidic patch with chromatin effectors
Recent studies have revealed the nucleosome acidic patch as a nexus for chromatin interacting proteins. Understanding the regulation underlying these binding events is critical to understanding of how genetic material is packaged and accessed in eukaryotes and how misregulation can lead to disease. It is well established that post-translational modifications (PTMs) of the histone tails help choreograph biochemical outputs on chromatin. By contrast, much less is known about how PTMs regulate access to the acidic patch, even though several modifications are proximal to this region. My research will combine the specificity of diazirine-based photocrosslinking reaction with high-throughput mass spectrometry-based techniques to accelerate the investigations into these regulations. The applications will be showcased in ascertaining the binding site between chromatin-remodeling proteins and the acidic patch, and a large-scale study to define the interactome of the acidic patch and chromatin effectors as the function of PTMs.
Division of Signaling and Gene Expression, La Jolla Institute for Allergy & ImmunologyRead more
Division of Signaling and Gene Expression, La Jolla Institute for Allergy & ImmunologySponsor: Anjana Rao
TET loss-of-function and R-loops-mediated genomic instability in cancer
The TETs (TET1, TET2, TET3) are epigenetic enzymes regarded as responsible for active and passive DNA demethylation, and are involved in a wide array of physiological and pathological cellular responses.
I have performed my Ph.D training in Prof. François Fuks’ laboratory in Belgium at the time that TET function was discovered by the team of Prof. Anjana Rao. Applying proteome and genome-wide approaches, we found that the most potent partner of TETs is the glycosyltransferase OGT (Deplus*, Delatte* et al., Embo, 2013), and I recently discovered that Tet is responsible for RNA hydroxymethylation in drosophila (Delatte et al., Science, 2016).
Therefore, I naturally couldn’t resist joining Anjana’s lab where I am now investigating the roles of TETs and hydroxymethylcytosine in genomic instability and cancer. I am also fascinated by the advances in next-generation sequencing, and am developing novel methodologies to map epigenetic modifications, but also identify diverse hallmarks of cancer such as DNA breaks or aberrant DNA:RNA structures.
Outside of the lab, I enjoy surfing, hiking, and particularly love watching movies with friends.
Department of Cellular and Molecular Pharmacology, University of California, San FranciscoRead more
Department of Cellular and Molecular Pharmacology, University of California, San FranciscoSponsor: Ronald Vale
Probe the interplay between actin cytoskeleton and immunoreceptor signaling
Department of Molecular Genetics and Cell Biology, University of ChicagoSponsor: Ed Munro and Sally Horne-Badovinac
Dissecting mechanical feedback in the Drosophila egg chamber
Department of Cell Biology, Harvard Medical SchoolSponsor: Wade Harper Co-Sponsor Joseph Mancias
Systemic analysis of the mammalian selective autophagy cargo network
The 2016 Nobel laureate Dr. Yoshinori Ohsumi remarked, “ Life is an equilibrium state between the synthesis and degradation of proteins”. My research focuses on Autophagy, a process whereby proteins are marked for destruction in cells by the lysosome. I became interested in autophagy during my PhD in Dr. Jim Haber’s lab at Brandeis University, and have been hooked on it ever since!
The autophagy-lysosome system targets the degradation of a specific cohort of proteins via “selective autophagy”. The dysfunction of this phenomenon has been linked to a myriad of human disorders. We have only scratched the surface of the known targets of this fascinating biological process. Under the guidance of my mentors, the aim of my research will be to comprehensively catalog the list of selective autophagy substrates by employing quantitative mass spectrometry of the autophagy-lysosome system. An overarching goal of my research is to obtain knowledge of the selective autophagic targets in cancer, which may present opportunities for the specific targeting of this process
I grew up in New Delhi, India. After completing my undergrad program in Biotechnology at the Vellore Institute of Technology in South India, I moved to the U.S. (Brandeis university, MA) for graduate studies. In my spare time, I am whittling down all of the 48 four thousand feet peaks in the White Mountain range while assiduously taking guitar lessons in the hope of one day playing lead guitar for a major rock band.
Department of Biology, University of VirginiaSponsor: Alan O. Bergland
Genetics and evolution of photoperiodism in Drosophila melanogaster
Organisms exhibit diverse strategies to survive environments that vary in space and time. In temperate climates, environmental cues are used to anticipate the onset of unfavorable seasons. One of the most reliable indicators of season is photoperiod: the length of light and dark periods within a 24-hour day. Insects exhibit a spectacular array of responses to changes in season. For example, aphids develop sexually reproducing morphs in the fall, moths and lacewings develop unique seasonal patterns and colors, monarch butterflies undergo seasonal migrations, and hundreds of species, including the fruit fly Drosophila melanogaster, are able to suspend development or reproduction until more favorable conditions return. Despite nearly a century of research on insect seasonality and photoperiodism, the genetic pathways used to make these ecologically crucial transitions remain unknown. The abundance of genetic and genomic resources for Drosophila makes it an ideal study system for this question.
My research uses custom-built environmental chambers, field studies in an experimental orchard, and novel genetic mapping techniques to dissect the genetic basis of photoperiodism and seasonal responses in Drosophila. Understanding how insects detect photoperiod will inform our understanding of economically and biomedically important insects and offer predictions about how insects may adapt to ongoing anthropogenic climate warming in which temperature, but not photoperiod, is changing.
Laboratory of Genetics, The Salk Institute for Biological StudiesSponsor: Fred Gage
Developing glial models in Parkinson's disease
Department of Cell Biology, Harvard Medical SchoolSponsor: Sichen Shao
Mechanistic dissection on nonsense-mediated decay
Division of Clinical Research, Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WashingtonRead more
Division of Clinical Research, Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WashingtonSponsor: David M. Hockenbery
The role of fructose in breast cancer growth by investigation of transcriptional regulation
With a high prevalence of sugar in our society, especially in the form of sugar-sweetened drinks, it is important to understand the relationships between sugar metabolism and critical events in cancer progression. Recent research shows that sugar metabolism can promote oncogenesis in cell culture models of breast epithelial cells. This research was done with the sugar glucose, but breast cancer cells also have the unique ability to uptake fructose, while normal breast epithelial cells do not. Fructose and glucose are both simple sugars that are present in equimolar amounts in most of the food we eat. Although fructose is naturally found in fruits and vegetables, it is also added as high fructose corn syrup to many drinks and processed foods. More research needs to be done on how cancer cells respond to conditions with fructose and glucose. I am using breast cancer cell culture models to investigate the effects fructose and glucose have on cancer cell growth. By focusing on differences in regulation of gene expression with exposure to different sugars, we aim to discover the mechanisms fructose uses to fuel cancer cell growth. We hope this work will lead to better informed dietary recommendations for breast cancer patients and those with an increased risk for breast cancer.
Hormone Institute and Diabetes Center, University of California San FranciscoRead more
Hormone Institute and Diabetes Center, University of California San FranciscoSponsor: Jeffrey Bluestone
Mapping and manipulating T-cell plasticity via synthetic receptor libraries
Immune dysregulation is implicated in a variety of diseases, and modulation of immune cell signaling has shown remarkable promise in the treatment of allergy, autoimmunity, and cancer. At the surface of each immune cell, hundreds of different receptors serve as the gateways through which information is recognized and integrated. These receptors are surprisingly modular and can be mutated and composed to rewire cellular inputs and outputs, as showcased by the success of cell-based genetic therapies like Chimeric Antigen Receptor T-cell (CAR-T) therapy.
My work combines computational protein design, chemical DNA library synthesis, and high-throughput pooled screening of millions of genetically modified primary human immune cells, each with different synthetic receptors. We are measuring these cells for differences in proliferation, differentiation, activation, and localization, both in vitro and in animal models. A better understanding of the relationship between receptor sequence, signaling outcome, and cellular phenotype will lead to next-generation cell-based genetic therapies which manipulate the immune system to combat a variety of diseases.
Department of Bioengineering, University of PennsylvaniaSponsor: Arjun Raj
Cellular states guiding plasticity and reprogramming paradigms in cancer
Department of Molecular and Cell Biology, University of California, BerkeleyRead more
Department of Molecular and Cell Biology, University of California, BerkeleySponsor: Xavier Darzacq and Robert Tjian
In-Vivo single-molecule imaging of enhancer-promoter communication
The different cell types in our body have an incredible variety of sizes, shapes, and functions, despite having the same genome. Differences between cell types arise from differences in which genes are transcribed into RNA. Transcription is regulated by DNA sequences called enhancers, which in some cases are located hundreds of thousands of basepairs away from their target genes. While we know the identities of many of these enhancers, and the proteins that bind to them, we lack a coherent model of how enhancers regulate transcription. Various lines of evidence suggest that large protein complexes form a bridge between enhancers and their target promoters. However, we lack a basic understanding of the composition, size, and internal organization of these enhancer-promoter complexes. Important questions are: 1) How many copies of different proteins assemble at enhancers and promoters? 2) What protein-protein and protein-DNA interactions are important for assembling enhancer-promoter complexes? 3) How dynamic are these complexes? 4) How do enhancer-promoter complexes ultimately regulate transcription? To address these questions, I am working to develop new fluorescence imaging approaches in live cells, which will combine fluorescent labeling of DNA, RNA, and protein with new technologies such as single-molecule tracking and lattice light sheet microscopy.
Department of Genetics, Stanford University, Stanford, California
Integrated omics of malignant transformation by breast cancer genes, with Michael Snyder
Through my clinical work with oncology patients I became acutely aware of how few interventions we are able to offer patients to prevent cancer. Even patients with inherited syndromes that confer a near-certainty of developing cancer have few, often unappealing, options to actually prevent cancer. This motivated me to investigate molecular mechanisms of the earliest steps of malignant transformation. I chose to study the genes causing inherited breast cancer because each one constrains the malignant phenotype of breast cells, an effect that can be modeled in vitro.
These ideas led me to team up with my advisor Dr. Michael Snyder at Stanford who has pioneered multiple high-throughput omics technologies to densely profile biological systems. These tools allow for an unprecedented window into cellular dynamics driving malignant transformation. I am particularly interested in how genomic aberrations in non-coding DNA elements can unlock transcriptional programs that drive malignancy. The hope is to uncover molecular switches that can be targeted to prevent cancer onset.
Whitehead Institute for Biomedical ResearchSponsor: Robert Weinberrg
Targeting the EMT program in high grade serous ovarian cancer
High-grade serous ovarian cancer (HGSOC) is the most aggressive gynecological malignancy for which few targeted therapies exist. The poor prognosis associated with this disease underscores the importance of targeting critical determinants of tumor relapse and therapeutic resistance, which account for the high morbidity rate. Given our lab’s findings that acquisition of the epithelial-to-mesenchymal transition (EMT) endows carcinoma cells with enhanced tumor-initiating potential and therapeutic resistance, I propose to identify novel mechanisms to reverse the EMT program by performing a pooled CRISPR/Cas9-based screen using a genome-wide sgRNA library optimized for high target cleavage efficiency. Candidate hits will be functionally characterized to ascertain their role in EMT-associated phenotypes and the mechanism by which their depletion elicits a mesenchymal-to-epithelial transition (MET). Furthermore, I will investigate the potential translation of these findings for therapeutic utility by evaluating the efficacy of tumor-targeting Layer-by-layer (Lbl) nanoparticles that deliver siRNAs or drugs that induce an MET alone or in combination with platinum-based drugs using clinically relevant HGSOC patient-derived xenograft mouse models and genetically engineered mouse models.
Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public HealthRead more
Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health
Role of the P13K-mTOR signaling network in reprogramming lipid metabolism
Department of Pharmaceutical Chemistry, University of California, San Francisco, CaliforniaRead more
Department of Pharmaceutical Chemistry, University of California, San Francisco, California
Within and between-cell effects of driver mutations on breast tumor fitness, with Zev Gartner
I am applying quantitative engineering approaches to study collective cell phenomena in cancer. Different cells in tumors develop different sets of mutations over time, creating a range of cell clones. One view of the role of cancer mutations is that they enable a small number of progressively malignant clones to take over the tumor one after another. However, mutations can have more complicated effects on tumor progression because their outward effects on the growth of a clone can depend on who their neighbors are. Therefore, I want to understand how cancer mutations affect the overall fitness of tumors by directly measuring it, not just in the cells that contain mutations, but also in neighboring cells. My research aims to shed light on how benign tumors make the transition to proliferative, invasive tumors; perhaps uncovering an Achilles heel to the manipulation of normal cells by mutant ones, leading to new types of cancer therapies.
Department of Genetics, Harvard University, Boston, Massachusetts
The role of organ communications in stem cell aging, with Norbert Perrimon
Adult stem cells are critical for maintaining homeostasis by repairing damaged tissues; however, this regenerative capacity of stem cells is affected with age, resulting in tissue degeneration. Age-related perturbations in stem cells are caused by changes in the intrinsic properties of the stem cells, in their niches and in the systemic milieu. In recent years, much has been learned about the pathways that control stem cell fate, lineage and proliferation. However, we know little about the mechanisms underlying age-related changes in stem cells. During my postdoctoral studies, I will investigate the mechanisms influencing the aging process of Drosophila midgut stem cells. In Aim1, I will determine the translatome of stem cells and their progenies during aging and regeneration. In Aim2, I will investigate the roles of inter-organ communication in stem cell aging and identify muscle-derived factors that coordinate gut stem cells aging with systemic aging. Finally, in Aim3, I will perform an unbiased genetic screen using transgenic RNAi lines to identify muscle-derived factors that influence gut stem cells aging. Together, these studies will identify regulatory networks affecting stem cell aging and provide novel insights for age-related diseases such as cancer.
Department of Systems Biology, Columbia UniversitySponsor: Saeed Tavazoie
Microbial adaptation to extreme environments facilitated by CRISP-Cas
Laboratory of Membrane Biology and Biophysics, The Rockefeller UniversityRead more
Laboratory of Membrane Biology and Biophysics, The Rockefeller UniversitySponsor: Jue Chen
Structural and mechanistic studies of multidrug resistance mediated by MRP1
Resistance to chemotherapeutic drugs is a major obstacle in the successful treatment of many different forms of cancer. This so-called multidrug resistance is often mediated by a class of proteins known as ABC transporters. These proteins reside in the plasma membrane and actively pump molecules out of the cell by utilizing the energy of ATP binding and hydrolysis. Some ABC transporters recognize and extrude anticancer compounds before they are able to kill the cancer cells, leading to drug resistance and treatment failure.
My project seeks to gain a better mechanistic understanding of these transporters and their role in multidrug resistance by utilizing a combination of structural and functional studies. My focus will be on the ABC transporter known as multidrug resistance protein 1 (MRP1). If we can better understand how these proteins are able to recognize and transport their drug substrates, we will be able to develop ways to block or circumvent their function during cancer treatment. If successful, these studies will not only further our knowledge of ABC transporter biology, but they will also lay a framework for combating multidrug resistance in cancer patients.
Department of Genetics, Stanford UniversitySponsor: Michael Bassik and Tony Wyss-Coray
Mechanistic dissection of mTOR and autophagy gene function in phagocytosis
Department of Pathology, Stanford UniversitySponsor: Hunter Fraser and Andrew Fire
Variation in chromosomal interactions in 10 human poplulations
Department of Psychiatry, University of California, San FranciscoRead more
Department of Psychiatry, University of California, San FranciscoSponsor: Frank Loren
Neural activity underlying individual variability in spatial decisions
Memory informs how animals interact with the world. It provides an expectation of the future based upon past experience. With navigation, animals draw upon a memory of their surroundings to inform their decisions. The hippocampus is critical for spatial decision-making by providing multiple ways to recall surroundings. Yet, why the hippocampus has multiple recall strategies remains unknown. To test the hypothesis that different recall strategies provide the substrate for individual variability, I will explore the behavior and hippocampal neural activity of both male and female rats during different spatial tasks. Beyond just recording the differences between animals, I will also specifically block hippocampal recall activity to determine their necessity for individual behavior. Studying individual decision-making will explore the range of neural computations that are consistent with normal functioning, and further our understanding of the complex relationship between the internal representation of the world and its external manifestations
Department of Biology, Stanford UniversitySponsor: Liqun Luo
Investigating cell type and brain circuit evolution in the cerebellum
Brain circuits and the neuronal cell types that form them are not static over evolutionary time. Rather, they cause and reflect the changing repertoire of animal behavior. How circuits and cell types change from their ancestral state to support novel behaviors during evolution, therefore, gives us important clues as to their current function. In my project, I will investigate the interaction between the cerebellum and the rest of the brain from this evolutionary angle by studying the progressive expansion and elaboration of the deep cerebellar nuclei, the output pathway of the cerebellum. I will profile transcriptional and projectional cell types of the DCN across species to probe changes in the DCN over deep evolutionary time. I will then integrate this dataset with developmental trajectories of the identified cell types in mouse, to provide mechanistic insight into how brain regions specialize on the level of single cells and circuit wiring to support new functions over the course of evolution.
Department of Biochemistry and Biophysics, University of California, San FranciscoRead more
Department of Biochemistry and Biophysics, University of California, San FranciscoSponsor: Jeremy Reiter
Centriolar satellites use phase separation to remodel the centrosome
Department of Chemistry and Chemical Biology, Harvard UniversitySponsor: Xiaowei Zhuang
Superresolution imaging of age related changes to the neuronal cytoskeleton
With global increases in average lifespan, understanding the neurological changes associated with normal aging has become increasingly relevant. Changes in neuronal architecture and synapse function have been proposed to underlie age related cognitive decline in healthy individuals, although the precise mechanisms remain unclear. The neuronal cytoskeleton is essential to the formation of unique neuronal architectures. Advances in superresolution microscopy have enabled the identification of an evolutionarily conserved Membrane-associated Periodic Skeleton (MPS) that forms an integral part of the neuronal cytoskeleton. Mutations in components of the MPS cause neurodegenerative disorders, suggesting that the presence of this network is also important for the maintenance of neuronal function. My project will focus on dissecting the functional role of age related changes to the MPS, providing us with a better understanding of the progressive loss in cognitive ability widespread in the aging population.
Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller UniversiyRead more
Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller Universiy
Structural and mechanistic principles of the HCN pacemaker channel
Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California, BerkeleyRead more
Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California, BerkeleySponsor: Kristin Scott
Maturation of neural circuits for memory
Adult behavior is the product of neural circuits that are wired during development and modified by experience. However, the mechanisms by which neural activity in early development affects circuit maturation to shape behavior remain poorly understood. My research investigates how neural activity in circuits for memory matures and sculpts learned behaviors. Using in vivo calcium imaging, genetic techniques and behavioral analyses in the Drosophila model system, I am characterizing developmentally regulated spontaneous neural activity in brain regions critical for learned behaviors and investigating how this activity shapes mature learned behaviors. I aim to identify molecular changes that trigger the maturation of memory circuitry and behavior. This research will increase our understanding of a fundamental mechanism relevant for normal brain development and may provide insights for translational research into its pathological misregulation in disorders of the nervous system.
Department of Biology, Koch Institute Massachusetts Institute of TechnologyRead more
Department of Biology, Koch Institute Massachusetts Institute of TechnologySponsor: Angelika Amon
Stem cell division and aging
Department of Immunobiology, Yale UniversitySponsor: Ruslan Medzhitov
Deciphering the mechanism and significance of stress tolerance
Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, New YorkRead more
Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, New York
Exploring the mechanism of skin stem cell regulation in skin wound repair, with Elaine Fuchs
Department of Chemical and Systems Biology, Stanford UniversitySponsor: Joanna Wysocka
Prion dynamics of transcription factors control cellular differentiation
I am interested in the prion dynamics of transcriptional regulators during human cell development. Lots of transcription factors contain low-complexity domains, which can drive the prion/granule formation. However, little is known about the prion functions or mechanisms of human transcriptional regulators. In our preliminary results, I found that some transcription factors form prions/granules at specific stages of the human neural crest differentiation process and the prions disappear rapidly afterwards. Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm cell layer, and in turn give rise to a diverse cell lineage. We hypothesize that the observed prion dynamics of transcription factors are crucial to the neural crest differentiation. As a postdoc in the Wysocka lab at Stanford, I will investigate the regulation factors of the observed prion dynamics as well as the molecular and developmental roles of these prions related to transcription regulation.
Department of Molecular and Cellular Biology, Harvard UniversitySponsor: Catherine Dulac
Neural control of social motivation
Social grouping offers social animals unique advantages to survive by decreasing energy consumption, reducing the risk of predation and promoting cooperation. Conversely, social disconnection or isolation can cause negative mental and physical results that motivate animal to re-engage in group. But how social motivation is encoded and regulated in neural circuit remains unclear. In this proposed project, I will identify the brain regions and cell types that are activated during social isolation and re-grouping. Utilizing cell-type targeted calcium imaging, I will monitor the neuronal dynamics during distinct social motivation states and specific social behavioral events. To further investigate underlying circuit-level mechanisms, I will examine the synaptic connections between regions associated with isolation and grouping, and how synaptic strength changes during social isolation. Finally, cell-type and projection specific optogenetic manipulations will be conducted to regulate social motivation and alter the relevant social behaviors. This project will shed new light into the regulation of social motivation both at the cell-type and circuit-levels.
Department of Pathology, Microbiology and ImmunologyRead more
Department of Pathology, Microbiology and ImmunologySponsor: Eric Skaar
Defining the clostridium difficile responses to zinc limitation
Clostridium difficile is an anaerobic Gram-positive bacterium responsible for nearly half a million intestinal infections in the U.S. annually leading to approximately 29,000 deaths. C. difficile infections (CDI) are most commonly triggered after disruption of the resident microbiota through antibiotics or chemotherapy, which allows C. difficile to subsequently colonize the intestines. CDI can manifest as a spectrum of disease, from mild diarrhea to pseudomembranous colitis or death. Even in situations where patients are treated, recurrent infections are common. While many of the risk factors for CDI are known, there is a general lack of understanding of why CDI presents as such a wide spectrum of disease and what the predictors are for recurrent CDI. My research is aimed at defining how C. difficile adapts to survive in the intestines to cause disease. By understanding the fundamental biology governing C. difficile interactions with the microbiota and the host in the context of infection, we can determine the predictors for disease severity or recurrence and guide the design of effective therapeutics.
Department of Bioengineering and Therapeutic Sciences, University of California, San FranciscoRead more
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco
My current research aims to explore how DNA regulatory elements influence human development and disease. I am particularly interested in identifying novel enhancers that regulate brain development and identifying mutations within them that lead to neurodevelopmental diseases.
I was born in Germany, where I studied Biology at the University of Goettingen and the University of Kiel. I then came to the US to pursue my Ph.D. in Human Genetics at the University of Utah. My graduate research in the lab of Dr. Mario Capecchi involved examining the role of Hoxa1, a homeobox transcription factor, in early brain development. This sparked my interest in the field of neuroscience and especially in development of the nervous system. I performed a postdoc in Dr. Liqun Luos lab at Stanford to study the connectivity of individual neurons in the brain. For my current postdoc in Dr. Nadav Ahituvs lab at UCSF, I am focusing on identifying gene regulatory elements that are involved in brain development and examining how changes in the genomic regulatory code can lead to specific phenotypes. Outside the lab, I enjoy the various outdoor activities that the Bay Area has to offer.
Department of Leukemia, MD Anderson Cancer CenterSponsor: Sean Post
hnRNP K: a putative driver of high risk DLBCL
Aggressive forms of diffuse large B-cell lymphoma (DLBCL) are often marked by genetic alterations at the MYC locus. However, only about 15% of de novo DLBCL cases actually harbor MYC alterations, yet MYC remains overexpressed in many cases alluding to the existence of uncharacterized mechanisms that facilitate its overexpression. Thus, there is a need to identify novel alterations that cause aberrant MYC expression in order to develop effective and targeted therapies. To this end, I have discovered that hnRNP K (Heterogeneous Nuclear Ribonucleoprotein K) is a novel driver of high-risk DLBCL. hnRNP K impacts lymphomagenesis by directly regulating the MYC oncogene via post-transcriptional mechanisms. Elevated MYC levels render hnRNP K-overexpressing cells sensitive to bromodomain inhibitors. Herein, I will determine the mechanistic basis for hnRNP Ks effect on MYC and test the preclinical efficacy of clinically relevant bromodomain inhibitors in hnRNP K-mediated DLBCL. Next, I will interrogate hnRNP K’s impact on therapeutic resistance to bromodomain inhibitors. Lastly, using a high-throughput fluorescence-based assay, I will identify novel compounds that directly disrupt the hnRNP K/MYC transcript interaction.
Department of Biological and Biolomedical Sciences, Yale UniversitySponsor: Wendy Gilbert
Defining the landscape and function of pseudouridines in pre-mRNA
Department of Molecular Biology, Massachusetts General HospitalRead more
Department of Molecular Biology, Massachusetts General HospitalSponsor: Gary Ruvkun and Vamsi Mootha
Molecualr mechanisms of oxygen sensation and mitochondrial dysfuntion
Molecular oxygen presents a fundamental biological problem: it is vital for life, yet also incredibly toxic. As the terminal electron acceptor in aerobic respiration and the redox engine of mitochondria, oxygen provides eukaryotes with the vast majority of their energy. However when molecular oxygen is reduced it can form damaging reactive species, and recent work has demonstrated that animals with genetic lesions in the mitochondrial respiratory chain are extremely vulnerable to oxygen toxicity. How animals have evolved to manage this double-edged sword remains a fundamental question.
The biology and natural ecology of the nematode C. elegans make it an attractive system in which to study oxygen tolerance. Wild type C. elegans are tolerant of oxygen concentrations ranging from 1% to 100%, and years of genetic studies have generated a rich toolbox of mitochondrial mutants. I will use these mutants to study the biology of oxygen tolerance, which may simultaneously shed light on the connection between mitochondrial disease and oxygen toxicity.
Skiball Institute of Biomolecular Medicine New York University Langone Health CenterRead more
Skiball Institute of Biomolecular Medicine New York University Langone Health CenterSponsor: Dan Littman
Uncovering the role of the inflammatory response in digit tip regneration
Several vertebrate species have the astonishing ability to regenerate their limbs following amputation. In mammals, including both mice and humans, this regenerative capability has been restricted to the digit tip. Both digit tip and complete limb regeneration follow a stereotypic process termed epimorphic regeneration where a population of progenitor cells, termed the blastema, form at the injury site to replace the multiple tissues lost (including blood vessels, nerves, bone, etc.). Several studies have demonstrated that macrophages are essential for epimorphic regeneration. However, it remains largely unknown how macrophages facilitate blastema rather than scar formation. Utilizing the mouse digit tip, which displays regenerative or scarring outcomes dependent on amputation site, we are functionally testing which immune cell types uniquely contribute to epimorphic regeneration. Furthermore, by combining diverse genetic tools with intravital imaging, we are beginning to understand how injury-induced inflammation yields a permissive tissue environment for epimorphic regeneration in mammals.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical SchoolRead more
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical SchoolSponsor: Johannes Walters
Mechanism of transcription-coupled DNA interstrand cross-link repair
Laboratory of Mammalian Cell Biology and Development, The Rockefeller UniversityRead more
Laboratory of Mammalian Cell Biology and Development, The Rockefeller UniversitySponsor: Elaine Fuchs
Dissecting the immune evasion mechanisms of tumorigenic stem cells
My research interest is to harness the power of immune system to combat cancer. This goal requires sophisticated understanding in both immunology and cancer biology. My prior graduate training has equipped me with extensive knowledge in immunology, and showed me how the immune system evokes robust and multilayered responses to defend our body against infections. However, compared to the vigorous response to infections, the immune system often becomes incompetent when it encounters cancer, especially malignant tumors. My goal during the fellowship period is to develop a cancer model in which I can trace the co-evolution between tumor-initiating stem cells and immune system, ultimately to the point of evasion of immune surveillance, so that I can identify the root of the blunted ant-tumor immune response during the cancer progression. With Dr. Fuchs’ expertise in epithelial stem cells and cancers, and my background in immunology, I feel that I’m uniquely poised to tackle this fascinating problem.
Department of Cellular and Molecular Biology, University of California, BerkeleyRead more
Department of Cellular and Molecular Biology, University of California, Berkeley
Pathogen-driven evolution of inflammasome genes
Department of Neurosciences, University of California, San DiegoRead more
Department of Neurosciences, University of California, San Diego
Top-down modulation of visual cortex during attention, with Massimo Scanziani
My general interest is how visual information interacts with non-visual information such as cognitive states to create our visual perception. In the lab of Massimo Scanziani, I am specifically focusing on how attention impacts visual processing in the mouse primary visual cortex. In humans and other primates, attention has been shown to increase the response of visually responsive neurons. It has been suggested that this modulation is mediated by feedback connections arising from higher cortical areas, yet the circuits and mechanisms remain poorly understood.
By using various in vivo and in vitro techniques available for the mouse, I plan on working out the cellular components of the circuit and determining its impact on the animals behavior during a task that requires attention. Through this study, I hope to advance our understanding of the basic principles of how cognitive states influence sensory perception.
Department of Molecular and Cell Biology, University of California, Berkeley, CaliforniaRead more
Department of Molecular and Cell Biology, University of California, Berkeley, California
Intra and trans-cellular mitochondrial communication in Parkinsons disease, with Andrew Dillin
Just like people, cells have to deal with stress. I study how stressed cellular organelles such as mitochondria communicate with the nucleus, and how this stress response is coordinated in normal settings and dysregulated in disease.
I studied genetics as an undergraduate at the University of California, Berkeley, and then worked at Sangamo BioSciences to help develop human genome editing with engineered nucleases. I was then an NSF Fellow in the Tetrad PhD program at the University of California, San Francisco, where I worked in Christine Guthries laboratory. There, I studied how pre-mRNA splicing is regulated in particular, how the cell coordinates a pre-mRNAs transcription and its splicing. My interest in how discrete molecular processes are integrated inside the cell continues during my postdoctoral fellowship in Andrew Dillins laboratory, where I am studying a remarkable pathway called the mitochondrial unfolded protein response. In this pathway, nuclear-encoded mitochondrial protein chaperones are upregulated in response to signals from mitochondria experiencing proteotoxic stress. I am using a disease-in-a-dish model that combines human stem cell technology with genome editing approaches.
Department of Chemical Biology and Therapeutic Sciences, Broad InstituteSponsor: David Liu
Continual evolution of proteins in eukaryotes
Department of Molecular and Cellular Biology, Havard UniversityRead more
Department of Molecular and Cellular Biology, Havard UniversitySponsor: Catherine Dulac
Characterizing the thermoregulatory circuits that control animal behavior
Thermoregulation is fundamental for survival; even slight changes in body temperature have a dramatic effect on vital processes such as sleep, appetite, and thirst, and during an immune response, febrile patients often become fatigued, antisocial, and exhibit other sickness-related behaviors. Specific brain areas are thought to control body temperature by triggering various mechanisms that produce or dissipate heat, but how thermoregulatory neurons modulate thermo-adaptive and other behaviors is unknown. I will use recently developed tools for genetic profiling and circuit analysis to molecularly identify thermoregulatory and fever-inducing neurons and map their connectivity patterns, thereby gaining new insight into thermoregulatory circuits and how they are connected to other homeostatic and social functions in the brain.
Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University, New York, New YorkRead more
Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University, New York, New York
Molecular mechanism of chloride ion transport by CLC protein family, with Roderick MacKinnon
My current research focus is on understanding molecular mechanisms of CLC proteins, ubiquitous membrane proteins that transport chloride ions across membranes. The CLC proteins are involved in various biological processes including regulation of membrane potential, electrolyte/fluid transport across epithelia, and control of intravesicular pH. Mutations in CLC genes cause many hereditary disorders in humans. An interesting aspect of the CLC family is that a common structural architecture seems to be used for both active and passive ion transport. Some CLCs are chloride channels, which provide a passive pore for chloride ion conduction, whereas others function as secondary active transporters that exchange two chloride ions for one proton. Despite recent advances in our understanding of their mechanisms, fundamental questions remain unanswered, especially regarding how exactly CLC transporters couple the transfer of chloride and proton ions and what leads to the mechanistic difference between the channels and transporters. In the MacKinnon lab, I use structural and functional approaches to address these questions.
Department of Molecular and Developmental Biology, University of California, Santa CruzRead more
Department of Molecular and Developmental Biology, University of California, Santa CruzSponsor: Manuel Ares
The impact of RNA polymerase II pausing on co-transcriptional splicing
RNA polymerase II (RNAPII) kinetics are well-known to influence splicing patterns. Recent evidence has revealed that many introns are spliced right after they are transcribed, opening the potential for cross-regulation between these two key processes. During transcription, RNAPII pauses during initiation and during 3’ end processing, and these pauses are thought to allow the recruitment of necessary protein factors. Although more transient, RNAPII also pauses throughout elongation, however the significance of these pauses is unclear. Importantly, many of these pauses occur near the exon-intron boundaries.
I am working to uncover the mechanisms that govern co-transcriptional splicing decisions. I am investigating the impact of RNAPII pausing on changes in splicing patterns using a short artificial arrest sequence, which allows me to engineer RNAPII pauses in any location. This DNA element, combined with improved genome-wide approaches such as Single Molecule Intron Tracking (SMIT), will allow me to assess how RNAPII pauses impact splicing patterns in both yeast and human cells.
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CaliforniaRead more
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California
Engineering novel allosteric control over synthetic T cell receptors to improve cancer immunotherapy, with Wendell Lim
I am interested in both the general biochemical principles that govern cellular signaling and the development of synthetic biology approaches to control complex signaling networks and cellular behavior. These interests are complimentary as synthetic biology is often informed by knowledge obtained from studying natural cellular signaling mechanisms refined by evolution. In Wendell Lims lab at UCSF, I am using this two-pronged approach to engineer new receptors and signaling networks to control the activity and behavior of therapeutic T cells. Such engineered multi-layered regulation of cellular activity — an important characteristic of naturally occurring biological systems — has the potential to make cell-based therapeutics safer and more effective, a critical concern for this burgeoning therapeutic approach.
I grew up in Louisiana, moved to Texas for undergrad and received my Ph.D. in Immunology from the University of Texas Southwestern Medical Center at Dallas (UTSW) in January 2013. There I studied fundamental cellular and biochemical mechanisms that regulate T cell activation at the systems-scale in Christoph Wülfings lab. Before graduate school, I did a wide-range of research. One of my major contributions was in Colleen McClungs lab in the Department of Psychiatry and Neuroscience at UTSW where I characterized the first mouse model resembling human mania caused by disruption of the circadian rhythm transcription factor, Clock. Outside of lab, I enjoy biking, climbing, and exploring the San Francisco Bay Area.
Integrative Structural and Computational Biology/Neuroscience, Scripps Research InstituteRead more
Integrative Structural and Computational Biology/Neuroscience, Scripps Research InstituteSponsor: Ardem Partapoutian and Andrew Ward
Molecular structure and mechanism of Piezo mechanotransdution channels
Piezo proteins are ion channels that sense mechanical force in various physiological pathways, including touch sensation, breathing, and vascular development. Mutations in Piezo cause diseases associated with mechanotransduction defects, including distal arthrogryposis and dehydrated hereditary stomatocytosis. Piezos are unrelated to other known ion channels, and how they transduce mechanical force into channel opening remains unknown. As a joint postdoc in Andrew Ward and Ardem Patapoutian labs, I use cryo-electron microscopy and other biophysical approaches to gain a mechanistic understanding of Piezo function.”
Division of Basic Sciences, Fred Hutchinson Cancer Research CenterRead more
Division of Basic Sciences, Fred Hutchinson Cancer Research CenterSponsor: Malik Harmit
Do genetic conflicts shape the actin cytoskeleton in eukaryotes?
I am interested in how evolution has shaped the eukaryotic actin cytoskeleton. The actin cytoskeleton is a critical force-generating polymer that powers fundamental cellular processes, including cell motility, vesicle transport and cytokinesis. Despite actins being among the most highly conserved proteins in eukaryotes, a number of actin variants and their regulators show strong signatures of genetic innovation in Drosophilids. Birth and death of novel actins have occurred between lineages and a few actin genes appear to rapidly evolve, suggestive of positive selection. Using genetic, evolutionary and cell biological analyses, I am investigating the evolutionary causes and functional consequences of genetic changes among components of the actin cytoskeleton with Drosophila melanogaster as the model organism. Exploring the actin cytoskeleton and its regulation from an evolutionary vantage will provide insight into the selective pressure on actins and how it is harnessed in many cellular processes.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical SchoolRead more
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School
Mechanism of incision-independent interstrand cross-link repair
Department of Molecular and Cellular Biology, University of California BerkeleyRead more
Department of Molecular and Cellular Biology, University of California BerkeleySponsor: Andrew Dilling
Defining the protective role of the mitochondrial stress response in aging
Department of Molecualr Biology and Genetics, Johns Hopkins University School of MedicineRead more
Department of Molecualr Biology and Genetics, Johns Hopkins University School of MedicineSponsor: Rachel Green
Defining mechanisms for selective translation in ribosomopathies
Labratory of neurosciences and behavior, The Rockefeller UniversityRead more
Labratory of neurosciences and behavior, The Rockefeller UniversitySponsor: Leslie Voshall
Arousal and motivation in the female mosquito
Female mosquitos seek out hosts for blood meals, a behavior that is required for reproduction and that evolved several times in insect evolution. Host seeking is a persistent behavioral state composed of sequential behaviors such as taking flight, searching, landing, and feeding. It is not known how these behaviors are coordinated nor how this persistent motivational state is signaled in the brain.
I propose to study sequential host-seeking behaviors by applying an automated behavior classification system to track multiple mosquitoes in three dimensions as they seek out and feed on a human host. Because of the important role of dopamine in insect decision making, I will use genetic approaches to manipulate dopamine signaling circuits in the mosquito Aedes aegypti. I will assess the effect of these perturbations during host seeking and during an assay simulating host defensive behavior. These experiments will give a description of the role of dopamine signaling in a sustained complex behavior that evolved in the common ancestor of mosquitoes.
Koch Institute, Massachusetts Institute of TechnologySponsor: Angelika Amon
Molecular basis of karyotype evolution in Ewing's sarcoma
Department of Biology, Massachusetts Institute of TechnologySponsor: Barbara Imperiali
Interrogating macromolecular interactions at biological membranes
I am passionate about biological processes that occur at cellular membranes. Membranes not only define the borders of cells but also create a fascinating physicochemical environment for a wide diversity of functions. The broad questions that I have been addressing focus on understanding the role of membrane lipids in the function of membrane peptides and membrane protein complexes and developing innovative methods for modulating lipid-peptide or lipid-protein interactions in order to control biological responses.
During my graduate research in France under the supervision of Prof. Solange Lavielle and Dr. Fabienne Burlina (at the École Normale Supérieure and the Pierre and Marie Curie University), I studied the spontaneous translocation of peptides through cell membranes that can be used as drug delivery agents. I characterized the translocation event at the molecular level, which provided pertinent clues to the design of drug delivery vectors with enhanced translocation abilities.
As a post-doctoral fellow in the laboratory of Prof. Barbara Imperiali (at Massachusetts Institute of Technology), my overarching goal is to decipher the organization and dynamics of supramolecular membrane protein complexes that are part of the N-linked protein glycosylation pathway of pathogenic bacteria. I propose to complement the current methods with an integrated strategy that will merge cell-free membrane protein expression, bioorthogonal labeling and membrane bilayer Nanodiscs. When combined, these technologies will give access to site-specifically labeled membrane-resident protein samples for detailed single-molecule biophysical analysis.
Department of Chemistry and Chemical Biology, Harvard UniversitySponsor: David Liu
Development of smart genome-editing agents for targeted therapy
Genetic abnormality is the root cause of many diseases. Canonical therapeutics primarily function by binding to the disease-associated proteins and modulating their activity. The recent advent of programmable sequence-specific endonucleases, however, has raised the possibility of direct manipulation of the corresponding genes and could eventually lead to effective cures of many diseases. The therapeutic potential of genome-editing agents is currently limited due to undesired DNA modifications including activity at off-target DNA sites and activity (on-target or off-target) in cells that are not the target population. My research focuses on developing genome-editing agents responsive to various endogenous and exogenous signals with improved specificity
Department of Molecular and Cell Biology, University of California, Berkeley, CaliforniaRead more
Department of Molecular and Cell Biology, University of California, Berkeley, California
Bookmarking the chromosomes and its role in cellular memory, with Robert Tjian
Cellular memory can be defined as the ability of a cell to transmit all its identifying functions to daughter cells during cell division. This ability to remember identity is crucial to the development of multicellular organisms, as evidenced when cells lose their identity and degenerate or become cancerous. Conversely, our ability to alter cell state, such as the generation of induced pluripotent stem (iPS) cells from differentiated cells, has become a promising therapeutic tool. Therefore, understanding how cells establish, maintain, and change identity will further our understanding of processes central to cellular development, disease progression, and therapy production. One mechanism for cellular memory is the ability to re-establish the transcriptional program following mitosis, which may function through bookmarking, the process of DNA-binding factors marking genes on condensed mitotic chromosomes to facilitate gene expression following mitosis. The main objective of this proposal is to analyze the mechanisms of bookmarking. I outline three independent approaches to characterize quantitatively the mechanisms of bookmarking. Using these approaches, I will test the hypothesis that histone variants and pluripotency factors function as bookmarkers to maintain the stem cell state. Lastly, I will perform an unbiased screen to identify putative bookmarking factors specific to embryonic stem cells.
Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer CenterRead more
Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer CenterSponsor: Scott Lowe
The role of ribosomal protein gene deletions in liver cancer
Department of Biology, Massachusetts Institute of Technology
Probing the role of peptidoglycan in establishing bacterial cell poloarity
Department of Bioinformatics, UT Southwestern Medical CenterSponsor: Gaudenz Danuser
Bleb-nucleated signaling scaffolds in metastasis-prone melanoma cells
Department of Microbiology and Immunology, Harvard Medical SchoolSponsor: John Mekalanos
Identifying novel nucleotide second messengers from mammals using bacteria
Nucleotide second messengers are crucial for development and signaling in both humans and bacteria. Nucleotide-centric pathways in human cells are targets of therapeutic interventions for cancer and diabetes, but signal regulation is complex and remains poorly understood. My work reconstructs mammalian nucleotide signaling in bacterial systems, creating the transformative opportunity to leverage bacterial genetics to uncover how these pathways are mechanistically regulated. Future findings from this work will enhance our understanding of known and previously uncharacterized cell signals in eukaryotes and prokaryotes.
Prior to my postdoctoral work, I earned my Ph.D. in Daniel A. Portnoy’s Lab, at the University of California, Berkeley. There, I worked on essential genes and virulence regulation in the bacterial pathogen Listeria monocytogenes.
Department of Neurobiology, Harvard Medical SchoolSponsor: Rachel Wilson
Investigating the role of decending neurons in flexible motor control
Department of Molecular and Cell Biology, University of California BerkeleySponsor: Kristin Scott
Sensory integration of taste and smell in drosphila
California Institute for Quantitative Biosciences, University of California, BerkeleyRead more
California Institute for Quantitative Biosciences, University of California, BerkeleySponsor: James Hurley and Roberto Zoncu
Mechanism of mTORC1 lysosomal recruitment via Rag:Ragulator
My current work focuses on understanding the molecular mechanism of mTORC1 activation and recruitment to the lysosome. Substrate phosphorylation by activated mTORC1 promotes cellular growth and inhibits catabolic pathways such as autophagy. The heptameric Rag:Ragulator complex in response to amino acids and growth factors binds and recruits mTORC1 to the lysosomal surface. Despite recent advancements in our understanding of the mTORC1 pathway, how this fundamental mTORC1:Rag:Ragulator complex forms is still poorly understood. Furthermore, a number of mutations have been identified within RagC for patients with follicular lymphoma which are thought to perturb this interaction hijacking the mTORC1 growth pathway. As a postdoctoral fellow in Hurley lab, my goal is to dissect the conformational states of mTORC1 throughout the activation pathway and capture the interaction with Rag:Ragulator
Laboratory of Neurogenetics and Behavior, The Rockefeller University, New York, New YorkRead more
Laboratory of Neurogenetics and Behavior, The Rockefeller University, New York, New York
Processing human cues in the mosquito brain, with Leslie Vosshall
Female mosquitoes require a blood-meal for reproduction, and show intense attraction to human hosts. They rely on host sensory cues, including carbon dioxide (CO2), and components of human body odor, such as lactic acid. These stimuli alone elicit little or no attraction, but in combination they synergize to trigger host-seeking behavior. After obtaining a blood-meal, female host-seeking behavior is switched off for several days. It is unknown where and how any human host cues such as, CO2 in breath, body odor, or body heat, are represented in the mosquito brain. It is also unknown how human host cues synergize to drive host attraction and ultimately trigger biting behavior, or how attraction is suppressed after a blood-meal. I will use two-photon excitation microscopy to measure activity in neural circuits in the mosquito brain to address these questions. This work will provide the first insights into how human cues are processed in the brain of the mosquito Aedes aegypti, which transmits Dengue Fever, Yellow Fever, and Chikungunya. The long-term aim of this research is to find novel approaches to intervene in mosquito biting behavior.
Department of Molecular and Cell Biology, University of California, BerkeleySponsor: Rebecca Heald
Uncovering molecular determinants of mitotic chromosome scaling
Our genomes are packaged into functional units of DNA called chromosomes, which are constantly being re-organized and re-shaped to match the demands of the cell. The most dramatic form of this reorganization happens as the cell prepares to divide: chromosomes are replicated, highly condensed, and aligned at center of the mitotic spindle, the complex protein-based machinery that physically separates exactly one copy of the genome to each daughter cell. Errors in this complex sequence of events can result in broken or rearranged chromosomes, known to be a significant source of mutations that drive the progression of many cancer types. A key factor in maintaining genome integrity during cell division is careful regulation of the length of the mitotic chromosome. In studies where chromosomes are artificially lengthened, the mitotic spindle fails at pulling the chromosomes apart, especially when certain cell cycle regulators are depleted. These results suggest that there are molecular pathways that can sense the physical dimensions of a chromosome and communicate this property to downstream regulators of the mitotic machinery. Yet, the exact dimensions being sensed and the molecules involved in this relay of information are still a mystery. Our goal is to identify the molecular pathways that sense, shape and re-enforce chromosome size during cell division. To do this, we will use the vertebrate model system Xenopus laevis, a powerful system for studying how physical dimensions of subcellular structures are determined during embryo development. Previous work from our lab has shown that mitotic chromosomes isolated from embryos in later stages of development are shorter compared to those isolated from early development. These results have provided a launching pad for our proposed work to now identify the molecular pathways that govern this change in size. We aim to (1) characterize how chromosomes are re-organized as they shrink, (2) find the molecules that contribute to these observed size changes and (3) implement the latest advances in imaging technology to test how changes in chromosome size affect embryo development. Because large-scale chromosome rearrangements are a driving force for many cancers, our findings will also provide a foundation for further research into how cancer cells hijack normal chromosome-size control pathways to continue growing and dividing. Also, since cellular behaviors during embryo development are very similar to those in a growing tumor, the tools we will develop to image chromosome dimensions in a growing embryo will greatly enhance our ability to visually assess large-scale chromosome rearrangements in cancer cells, both for research and diagnostics purposes.
Department of Microbiology and Immunology, University of California, San FranciscoRead more
Department of Microbiology and Immunology, University of California, San FranciscoSponsor: Alexander Johnson
Molecular analysis of bistability in a eukaryotic transcriptional network
Transcription circuits, defined as transcription regulators and the DNA cis-regulatory sequences they bind, control the expression of genes and define cellular identity. In eukaryotic cells, regulatory networks tend to be large, containing many highly interconnected transcription factors. Many of these complex networks are bistable, meaning they can toggle between two stable steady states. Bistable networks are responsible for such varied processes such as irreversible decisions during cell cycle progression, embryonic stem cell differentiation and oocyte maturation.
I study a bistable transcriptional network in the human commensal yeast Candida albicans that controls an epigenetic switch between two distinct cell types. This network shows many features of those in higher eukaryotes including the high degree of stability of each cell type. The goal of my research is to gain a molecular understanding of the functional differences between the multiple feedback loops present in bistable transcriptional circuits. This analysis will serve as a model for the general understanding of complex circuits.