Directory

Soo Hee Lee Jane Coffin Childs Fellow

Yale University / University of Texas Southwestern Medical Center
Appointed in 2008

Sponsor: Elisabetta Ullu and Christian Tschudi

I am trying to figure out what an Argonaut-like protein is doing in the mitochondrion of the sleeping sickness parasite, Trypanosoma brucei.

I did my graduate work at the Johns Hopkins School of Medicine, in the Department of Biological Chemistry, where I worked on trypanosome fatty acid synthesis.  Protozoan parasites that cause human disease—i.e. malaria, Chagas disease, leishmaniasis, and sleeping sickness—are not only relevant medically, but often have surprising and unusual biologies that fill pieces of the larger picture of our own evolution.  For example, GPI anchors were first discovered in T. brucei and have a specific role in parasite evasion of the host immune system.  Besides my fascination with the biology of the bizarre, I enjoy living in New Haven with my dog Jack.

Joyce Lee, Ph.D. Jane Coffin Childs - HHMI Fellow

Dana-Farber Cancer Institute
Appointed in 2022

Sponsor: David Pellman

Common fragile sites (CFSs) are hotspots for genomic rearrangements in cancers, but why and how these rearrangements occur is poorly understood. CFSs are characteristically difficult to replicate and often persist as under-replicated DNA into mitosis. Previous work from my host laboratories showed that stalled DNA replication forks are disassembled upon exposure to the mitotic kinase Cyclin B-CDK1. Unloading of the replisome leads to the formation of DNA breaks at the stalled forks followed by break-end ligation events. Coordinated DNA repair events at converging stalled forks in mitosis could lead to the formation of deletions and sister chromatid exchanges, both of which are signatures of CFS expression.

Recent studies have shown that CIP2A is a mitosis-specific repair factor that localizes to sites of DNA damage and replication stress. My aim is to investigate the role of CIP2A in cellular responses to unreplicated DNA in mitosis and how these processes contribute to genomic instability at CFSs. I will use the Xenopus egg extract system to uncover the biochemical mechanism of CIP2A function and conduct cell-based studies to observe the effects of CIP2A on genome stability.

Sarah Leinwand Jane Coffin Childs Fellow

University of California, Berkeley
Appointed in 2016

Sponsor: Kristin Scott

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.

Duncan Leitch Jane Coffin Childs - Simons Foundation Fellow

University of California, San Francisco
Appointed in 2014

Sponsor: 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.

Leonetti Leonetti Jane Coffin Childs - HHMI Fellow

University of California, San Francisco
Appointed in 2013

Sponsor: 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 Jane Coffin Childs - HHMI Fellow

Rockefeller University
Appointed in 2014

Sponsor: 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.

Jiefu Li Jane Coffin Childs - HHMI Fellow

Stanford University
Appointed in 2020

Sponsor: Mark Davis

T lymphocytes are central players of our adaptive immune system for fighting against pathogens as well as aberrant self cells. The recognition, action, and modulation of T cells rely on diverse molecules on their surface, including T cell antigen receptors (TCRs) and numerous signaling modulators, such as CTLA-4 and PD-1. Using systems approaches, I study cell-surface signaling of human T cells, with two focuses: 1) I combine TCR repertoire profiling, computational analysis, and scalable antigen screen to quantify TCR repertoire dynamics in infectious diseases and search for population-shared antigens to inspire vaccine development; 2) I build novel tools for spatiotemporally-resolved quantitative proteomics to determine how the T cell surface proteome evolves under distinct cellular states and look for molecular targets for invigorating or modulating T cell activities.

Gen Li, Ph.D. Jane Coffin Childs Fellow

University of California, Berkeley
Appointed in 2022

Sponsor: Christopher Chang

It has long been a focus for the identification of protein drivers and for the development of corresponding cancer therapeutics. Traditionally, drug discovery efforts mainly rely on “druggable” proteins, which possess easily identifiable binding pockets or catalytic active sites. However, over 85% of the proteome is still considered “undruggable”, posing additional challenges for further development. Recently, Activity-Based Protein Profiling, has arisen to spotlight the undruggable proteome via covalent linkage of reactivity-based chemical probes and “ligandable hotspots” in the proteome. In the proposed research, I aim to develop new chemoproteomic platforms based on inexpensive and biocompatible main-group molecules for chemoselective methionine and methionine sulfoxide bioconjugation, to further promote cancer drug discovery. This contribution will be significant because it can develop a ligandability map against undruggable proteome, serve as efficient tools in cancer cell early-stage diagnosis, and further provide a handle to decipher and drug methionine redox regulation in cancer cells, thus yielding novel therapeutics.

Brian Liau Jane Coffin Childs Fellow

Massachusetts General Hospital
Appointed in 2014

Sponsor: 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.

Louisa Liberman Jane Coffin Childs Fellow

Duke University
Appointed in 2010

Sponsor: Philip Benfey

My current research involves investigating cell-type specific growth regulation in response to cross-kingdom communication in Arabidopsis thaliana.  I am interested in learning about the signaling that occurs between plants and microbes in the soil resulting in developmental and physiological changes in the plant.

Raised in Lexington, Massachusetts, I attended Mount Holyoke College, from which I graduated with a double major in biological sciences and Spanish.  I received my PhD working with Angelike Stahopouolos at the California Institute of Technology.

I have always loved puzzles and nature.  Being a scientist means that I have the opportunity to ask questions and learn about how organisms develop and adapt to their environments.  I was drawn to a career in biology because it appeals to my curiosity and provides exciting possibilities to explore what we do not know about nature. When not engaged in my research, I like to spend time outdoors, particularly gardening.  I also enjoy running, biking, skiing, and swimming.

Wen-Hui Lien Jane Coffin Childs Fellow

Rockefeller University
Appointed in 2010

Sponsor: Elaine Fuchs

Current research: Understanding differential roles of Wnt signaling ¬ó beta-catenin-Lef/TCF complex in regulation of epidermal homeostasis, hair follicle stem cell maintenance and activation.

My interests in science started in elementary school in my home town of Tapei, Tawain. Later, when my beloved grandfather died of cancer, I was inspired to understand cancer biology.

At Kaohsiung Medical University I did research in molecular biology, for which I received the Undergraduate Innovative Research Award from Taiwan’s National Science Council. During my graduate research at the Institute of Molecular Medicine in National Chung Kung University, I became interested in understanding how tumor cells escape from different cancer therapies.

When I came to the U.S., I spent a year at the Fred Hutchinson Cancer Research Center (FHCRC) in Seattle, where my research was to identify novel genes that inhibit myc-induced apoptosis.   My PhD dissertation research at the University of Washington / FHCRC focused on understanding underlying mechanisms and physiological significance of the cell adhesion protein, aE-catenin. After obtaining my PhD in 2008, I received the 2009 Harold M. Weintraub Graduate Student Award.  In April, 2009 I joined the laboratory of Elaine Fuchs at Rockefeller University.

Jaechul Lim Jane Coffin Childs Fellow

Yale University
Appointed in 2018

Sponsor: Ruslan Medzhitov

Cells continually encounter a variety of suboptimal conditions which restrict growth and proliferation. In response to such stressors, proper adaptive mechanisms are typically activated, which can be categorized into two groups, specific and general. The stress-specific responses, such as DNA repair or unfolded protein response, directly deal with the primary cause. By contrast, a common response is assumed to inhibit growth and render cells highly tolerant to the stress as a dormant state of an organism. While most studies have focused on the stress-specific responses, little is understood about how cells initiate and maintain the common program of stress tolerance. By analyzing sequencing data on various stress conditions, I have found several genes that are commonly regulated in mammalian cells. I hypothesize those genes may modulate stress tolerance which may protect cells from stressors. To understand the role of those candidates, I will 1) determine their targets to unveil regulatory networks and 2) perform in vivo experiments with various stresses to confirm whether the candidates function in the physiological context. By understanding the core stress response, this research will address an important but often overlooked as standing of cell survival and maintenance.

John Lin-King, Ph.D. Jane Coffin Childs - Merck Fellow

Stanford University
Appointed in 2021

Sponsor: Chen Xiaoke

Chronic pain affects approximately 20% of the adult population in the United States (~50M people), incurring an annual economic impact exceeding 3% US GDP (~$600Bn). This critical public health issue lacks effective treatments beyond classic opiate-based therapies, which itself is a major underlying contributor to the development of the opiate addiction epidemic. Our laboratory has previously found a population of neurons, which are marked by the expression of an opiate receptor and which project from the brainstem to the spinal cord, that are required to facilitate the development chronic pain. We are currently seeking to gain insights into the molecular mechanisms of how these neurons facilitate chronic mechanical hypersensitivity after nerve injury.

More specifically, we have carried out transcriptional profiling of these neurons and found that they selectively upregulate a handful of neuropeptides in the chronic pain state. Currently, we are using RNA-interference to characterize the contribution(s) of individual neuropeptides to the development of chronic pain. With this data in hand, we next aim to identify the cells and corresponding neuropeptide receptor(s) in the spinal cord that are innervated by these neurons. In this way, we will define the peptide-based circuit from brainstem to spinal cord that acts as a gate for the development of chronic pain. Success of this aim will describe a new signaling pathway and therapeutic target(s) that underly the development of this devastating condition.

Chi-Yun Lin, Ph.D. Jane Coffin Childs Fellow

Pennsylvania State University
Appointed in 2021

Sponsor: Joseph Bollinger

Protein-based radicals participate in biological processes and natural product biosynthesis that link to life and death in organisms. One remarkable example is class I ribonucleotide reductases (RNRs), which catalyze DNA synthesis with tyrosyl radical relays. To compete for available resources, particularly in pathogens that live in the context of a host, RNRs have evolved distinct cofactors, assembly strategies, and radical translocation mechanisms. Understanding these distinctions from human counterparts is a key step in developing successful anticancer, antimicrobial, and antiviral drugs that inhibit RNRs. However, tyrosines are abundant and form highly cooperative networks, presenting difficulties in isolating their contribution to vectorial redox. I aim to dissect these tyrosines in the newly discovered class I RNRs to probe the free energy landscape of their one-electron oxidation and determine the active state structures. To further advance the field of redox enzyme design for difficult chemical reactions, I will elucidate the crucial protein environmental factors that modulate productive tyrosyl radical relays and prevent detrimental side reactions.

Xinyu Ling, Ph.D. Jane Coffin Childs - Merck Fellow

Broad Institute of MIT and Harvard
Appointed in 2023

Sponsor: Dr. Bo Xia

Transposable elements (TEs) play a crucial role in genomic regulation by affecting gene functions, particularly in alternative splicing (AS). Among these, intronic TEs are notably abundant in the human genome, numbering over a million instances. Current research has predominantly fixated on individual TEs near splicing sites, neglecting the vast majority of deep intronic TEs. This oversight hampers our understanding of their collective impact on AS and their relevance to developmental and disease phenotypes. To address this gap, we first start with examining the interaction of TEs within the TBXT gene. TBXT is vital in embryonic development and implicated in tail loss in hominoids and chordoma, a bone cancer where TBXT is aberrantly activated. Exploring these interactions will deepen our knowledge of AS regulation and provide insights into personalized cancer treatment by identifying new genetic markers and therapeutic targets. This research seeks to provide a novel framework to study how the interaction between TEs can affect gene function by modulating pre-mRNA splicing. By uncovering the intricacies of TE-induced AS, we seek to unearth new genetic markers and therapeutic targets, offering novel avenues in disease treatment and prevention.