Directory - Jane Coffin Childs Memorial Fund

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Elio A. Abbondanzieri, Ph.D. Jane Coffin Childs Fellow

Harvard University

Project Title: A single-molecule study of reverse transcriptase

Mohamad Abedi, Ph.D. HHMI - Jane Coffin Childs Fellow

University of Washington

Project Title: In situ engineering of speciﬁc cells with de novo designed protein logic

Despite the tremendous efforts spent towards genetically reprogramming T cells for therapeutic purposes, the complex ex vivo procedures and costs involved in producing genetically modified lymphocytes remain major obstacles for implementing them as a standard of care in the treatment of cancer. As a JCC fellow, my goal has been to bypass these obstacles by developing a technology that combines designed protein logic with engineered viruses to target and genetically engineer specific cell populations in vivo. To achieve targeted cellular engineering in vivo, I adapted a co-localization dependent protein switch, named Co-LOCKR, that classifies cells based on their receptor expression. Upon locating cells with the correct receptor combination, Co-LOCKR presents a target peptide that guides engineered viruses to genetically modify tagged cells.

Herbert T. Abelson, M.D. Jane Coffin Childs Fellow

Massachusetts Institute of Technology

Project Title: Nucleic acid antagonists at the subcellular level

Emma Abernathy, Ph.D. Jane Coffin Childs Fellow

Stanford University

Project Title: 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‚Äôm 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‚Äôm 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.

Image of Stephen K. Abini-Agbomson, Ph.D.

Stephen K. Abini-Agbomson, Ph.D. Jane Coffin Childs Fellow

Max Planck Institute of Immunobiology and Epigenetics

Project Title: Direct Visualization of DNA Methyltransferase Oligomerization and Its Influence on Neuronal Gene Regulation

Epigenetic modifications are changes that affect how our genes are turned on or off,
without changing the underlying DNA sequence. These changes can be influenced
by factors like our environment, diet, and lifestyle. The epigenetic modifications of
DNA and chromatin-associated proteins play a crucial role in regulating cell-type
specific gene expression. Methylation of DNA, for example, is associated with
turning genes off via transcriptional repression. In most cells, DNA methylation
occurs in the context of “CG” dinucleotides. Neurons, however, are also methylated
at “CA” sequences.

Dr. Stephen Abini-Agbomson predicts that the oligomerization, or the
process of small molecules joining together to form a larger structure, of DNA
methyltransferases (DNMT) is important for their appropriate genomic localization
and activity. He will use cutting edge single-molecule approaches to investigate the
role of DNMT oligomerization in gene expression during neuronal development
in Dr. Ibrahim Cissé’s lab at the Max Planck Institute of Immunobiology and
Epigenetics. Mis-regulation of DNA methylation is frequently observed in
neurodevelopmental disorders and many types of cancer. Dr. Abini-Agbomson’s
findings may produce new mechanistic insights to inform future therapeutic
targeting of these diseases.

Abini-Agbomson honed his expertise in epigenetics and chromatin biology as
a graduate student in Dr. Karim-Jean Armache’s lab at the New York University
Grossman School of Medicine. There, he demonstrated that the histones encoded
by giant viruses can form nucleosomes. This was quite surprising as previously it
was thought that only eukaryotes have nucleosomes. Additionally, Abini-Agbomson
showed that the lysine methyltransferase SUV420H1 impacts chromatin dynamics
through both enzymatic and non-enzymatic mechanisms. With this research
background, Abini-Agbomson is poised to make breakthrough discoveries on the
impact of epigenetic protein oligomerization in neurodevelopment.

Keith L. Adams, Ph.D. Jane Coffin Childs Fellow

Iowa State University

Project Title: Expression of genecin in allopolyploids

Paul N. Adler, Ph.D. Jane Coffin Childs Fellow

University of California, Irvine

Project Title: Imaginal discs of D. Melanogaster

Lauren C. Aguado, Ph.D. Jane Coffin Childs Fellow

Rockefeller University

Project Title: Entering the unknown: How do viruses transition to new hosts?

All viruses require the vast resources of a cell to complete their lifecycles, carrying with them only the tools essential for their replication that cannot be found in a host. While many viruses infect only a single or few closely related species, arboviruses constantly cycle between an insect vector and a vertebrate host. This requires that a virus be able to take advantage of two unique cellular environments while evading entirely different defense systems to do so. Many of the host factors essential for viral replication in the insect vectors remain entirely unidentified; of those that have been defined, only a subset is required in both insect and vertebrate species. Many more are utilized in only one species, leading to the hypothesis that arboviruses have found multiple ways to achieve the same ultimate goal of replication and dissemination in these dual hosts. My work seeks to understand how these disparate environments can support the replication and transmission of a single virus and how viruses can adapt to new host species.

Hugo G. Aguilaniu, Ph.D. Jane Coffin Childs Fellow

Salk Institute for Biological Studies

Project Title: The genetics of dietary restriction

Green Ahn, Ph.D. HHMI - Jane Coffin Childs Fellow

University of Washington

Project Title: De novo design of extracellular effector for modulating distinct outputs of cell-surface proteins

Cell surface proteins can drive diametrically opposed phenotypic outcomes when bound by ligands, distinct molecules that attach to other specific molecules. Therefore, efforts to rewire membrane protein signaling, introducing a specific function could improve and change how we develop treatments.

Dr. Green Ahn will engineer novel membrane protein effectors in Dr. David Baker’s lab at the University of Washington. Using artificial intelligence protein design tools, Dr. Ahn will design a library of de novo extracellular effectors against particular ectodomains of cell surface proteins and investigate how those effectors impact downstream function. Ahn’s studies will provide fundamental insight into membrane protein signaling and set the stage for future therapeutic targeting of these pathways.

Ahn’s expertise in targeting membrane proteins stems from her graduate studies in Dr. Carolyn Bertozzi’s lab at Stanford University. There Ahn developed the first cell-type-specific degrader for a membrane protein. Ahn built on that study to discover cellular factors that are required for targeted membrane protein degradation. She also helped develop the first de novo designed proteins that trigger membrane protein degradation in collaboration with Dr. David Baker’s lab. With this experience Dr. Ahn is poised to make future discoveries with implications for our fundamental knowledge of protein membrane biology as well as future therapeutic strategies.

Bassem Al-Sady, Ph.D. Jane Coffin Childs Fellow

University of California, San Francisco

Project Title: Investigating the core mechanisms of heterochromatin formation

James L. Alderfer, Ph.D. Jane Coffin Childs Fellow

Johns Hopkins University

Project Title: Physicochemical properties of ribopolymers

Patrick N. Allen, Ph.D. Jane Coffin Childs Fellow

University of Colorado, Boulder

Project Title: Interactions between nucleic acid ligands and HIV-1 proteins

Gregory M. Allen, M.D., Ph.D. Jane Coffin Childs Fellow

University of California, San Francisco

Project Title: Synthetic control of immune cell trafficking

Cellular therapy, exemplified by chimeric antigen receptor (CAR) T cells, is an emerging class of therapeutics that applies the principles and techniques of synthetic biology to the treatment of disease. Although promising clinical results have been obtained with CAR T cells in B Cell lymphoma and leukemia, substantial work remains to create cellular therapies that can effectively treat solid tumors. In part this is due to a lack of robust mechanisms to control spatial location of cells, which can diminish efficacy, increase toxicity and limit more sophisticated future therapeutic applications. In my research I am interested in genetically modifying T cells to create user-defined synthetic trafficking functionalities in order to promote solid tumor infiltration. In addition I am developing syngeneic mouse tumor models to synthetically control the migratory signals (chemokines) in a tumor in order to map the migration ‚Äúcode‚Äù a tumor uses to control the immune system. These projects have the potential to form the basis of the next generation of adoptive cellular therapies and illuminate the mechanisms that the tumor microenvironment uses to regulate the endogenous immune system.

Ibraheem S. Alshareedah, Ph.D. HHMI - Jane Coffin Childs Fellow

Boston Children's Hospital/Harvard Medical School

Project Title: Protein-DNA interactions in DSB repair accross scales

Homologous recombination (HR) is an important pathway for error-free DNA strand break repair. Proper repair of DNA breaks is crucial for preventing cancer, as indicated by the number of frequent genetic mutations in this pathway that lead to breast, ovarian, and other types of cancer. Therefore, a better mechanistic understanding of DNA break repair may open up new avenues for therapeutic targeting of cancer.

Dr. Ibraheem Alshareedah is taking a novel approach to investigate DNA break repair in Dr. Taekjip Ha’s lab at Harvard Medical School. It is known that BRCA2 loads RAD51 onto single-stranded DNA (ssDNA), yet HR still occurs in BRCA2-mutant cancers, suggesting that there is redundancy in this pathway. Dr. Alshareedah hypothesizes that RAD52 nanoclusters in cells recruit RAD51 and load it onto ssDNA, even in the absence of functional BRCA2. To investigate this hypothesis, Alshareedah will examine if RAD51, ssDNA, and other DNA-break repair proteins are recruited to RAD52 nanoclusters in cells. He will then determine which RAD52 protein features are required for cluster formation. By understanding the partial redundancies in the DNA repair pathway, Alshareedah’s research may reveal novel targets for treating BRCA2-mutant cancers.

Alshareedah’s expertise in protein and nucleic acid clusters stems from his Ph.D. research in Dr. Priya Banerjee’s lab at the University at Buffalo. There, Alshareedah focused on the formation and material properties of protein-nucleic acid biomolecular condensates. He developed an in-condensate passive micro rheology assay and showed that condensates behave as an elastic solid on short time scales, but like a viscous liquid on long time scales. Alshareedah also used this method to probe the aging process of condensates, which is thought to be related to protein aggregation in neurodegenerative diseases. Now in his postdoctoral research, Alshareedah will investigate the functional importance of RAD52 condensates in BRCA2-mutant cancers.

Thomas H. Alton, Ph.D. Jane Coffin Childs Fellow

Stanford University

Project Title: Organization and expression of D. discoideum genome

Aurora Alvarez-Buylla, Ph.D. Jane Coffin Childs Fellow

University of California, Berkeley

Project Title: Harnessing long-range hormone signaling for therapeutic delivery

What do poisonous frog toxins have to do with drug delivery? More than you might think, according to Jane Coffin Childs Fellow Dr. Aurora Alvarez-Buylla.

During her thesis research in Dr. Lauren O’Connell’s lab at Stanford, Alvarez-Buylla identified the first toxin binding protein in poison frogs. This protein, a serine protease inhibitor, or serpin, binds to toxins in the blood, and delivers them to skin glands for bioaccumulation. Interestingly, Alvarez-Buylla found that this frog protein is very similar to mammalian hormone carrier proteins that facilitate the transport of lipid-soluble hormones in the bloodstream and their delivery to target cells.

For the fellowship in Alanna Schepartz’s lab, Dr. Alvarez-Buylla plans to reconstruct the evolutionary trajectory of mammalian hormone carrier proteins. Like frog poison, many therapeutics are toxic when delivered systemically, therefore it is desirable to sequester these therapeutics until delivered to a particular organ. By understanding the range of small molecules that these proteins could possibly bind to, and how their release can be triggered, Alvarez-Buylla’s research will establish a framework for rationally engineering proteins to serve as novel drug delivery agents for many therapeutic molecules.

Jeanine F. Amacher, Ph.D. Jane Coffin Childs - Frederic M. Richards Fellow

University of California, Berkeley

Project Title: Substrate docking and ubiquitylation in the E3 ligase Cbl

Post-translational modifications regulate key interactions in signaling pathways. In protein tyrosine kinase (PTK) signaling, for example, crosstalk between phosphorylation and ubiquitylation signals is critical to proper cellular function. A phosphorylation cascade is triggered upon PTK activation; in turn, the RING-type E3 ubiquitin ligase Cbl is activated, and attenuates many of these signals via lysosomal degradation. In cancers where there are mutations in PTK signaling, this communication breaks down, leading to uncontrolled cell proliferation and poor patient prognosis.

During my postdoctoral work in Dr. John Kuriyan¬ís lab at UC Berkeley, I am using biochemical assays and X-ray crystallography to better understand the regulation and selectivity of Cbl with respect to its targets. Cbl has a unique activation mechanism, whereby substrate docking is followed by phosphorylation at a conserved tyrosine residue, turning Cbl ¬ìon.¬î I hypothesize that crosstalk between Cbl¬ís tyrosine kinase binding and RING domains dictates its selectivity and regulates substrate kinase activity. PTK signaling is a finely tuned product of evolution, and a greater understanding of how Cbl interacts with its substrates will unveil new possibilities for intervention.

Enrique Amaya, Ph.D. Jane Coffin Childs Fellow

University of California, Berkeley

Project Title: Cell interactions patterning the vertebrate embryo

John E. Amoore, Ph.D. Jane Coffin Childs Fellow

University of California, Berkeley

Project Title: Effect of oxygen-lack on mitosis

Karin Anderson, Ph.D. Jane Coffin Childs Fellow

Dana Farber Cancer Institute

Project Title: Movement of hnRNP proteins in and out of the nucleus

Margaret LM. Anderson, Ph.D. Jane Coffin Childs Fellow

Cold Spring Harbor Laboratory

Project Title: Control of protein synthesis in a cell-free system

Douglas A. Andres, Ph.D. Jane Coffin Childs Fellow

University of Texas Southwestern

Project Title: Purification of farnesyl-cysteine protease

Robin J. Andy, Ph.D. Jane Coffin Childs Fellow

New York University

Project Title: Targeting of cloned beta glucuronidase to lysosomes

Esther R. Angert, Ph.D. Jane Coffin Childs Fellow

Harvard University

Project Title: Identification of cell division genes in Epulopiscium

Image of Andrew V. Anzalone, M.D., Ph.D.

Andrew V. Anzalone, M.D., Ph.D. Jane Coffin Childs - HHMI Fellow

Broad Institute

Project Title: Genome editing with single nucleotide precision

Image of Eftychia (Effie) Apostolou, Ph.D.

Eftychia (Effie) Apostolou, Ph.D. Jane Coffin Childs Fellow

Massachusetts General Hospital /
Harvard Stem Cell Institute

Project Title: Differentiation hierarchy and reprogramming potential in hematopoietic cells

My current research focuses on the molecular and epigenetic mechanisms governing the process of nuclear reprogramming of somatic cells into induced pluripotent stem cells (iPS cells). More specifically, I study how the differentiation stage of the initial somatic cell affects the efficiency of reprogramming into iPS.

I was born at Naoussa, a small town in northern Greece. I studied biology at Aristotle University of Thessaloniki and pursued my PhD on molecular ¬†biology at the medical school of the National University in Athens. While working at Dr. Dimitris Thanos¬í lab for my PhD thesis — In vivo study of the dynamics of transcriptional ¬†¬†complexes” — I became intrigued by biochemistry and familiar with molecular and cytogenetic techniques. ¬†I also published my first paper, which ¬†opened the door to Harvard University and a new world. ¬†I switched my scientific focus to this new and exciting field. I joined Dr. Konrad Hochedlinger¬ís lab and am more than happy with my choice. At the beginning of my second year, I feel so much richer in knowledge and research experience. I also enjoy life in Boston, which is an ideal city for tango dancing and hiking.”

Julie E. Archer Mayo, Ph.D. Jane Coffin Childs Fellow

California Institute of Technology

Project Title: Biochemical analysis of anaphase promoting complex

Kevin Aris, Ph.D. Robertson Foundation-Jane Coffin Childs Fellow

University of California, Berkeley

Project Title: Exploring the epigenetic role of DNA topology in gene regulation and disease

DNA usually forms a right-handed double-helix, known as the canonical B-form. But DNA can also be wound more tightly or more loosely, called positive and negative supercoiling. DNA supercoiling can impact how genes are regulated yet is difficult to study in its native cellular context.

During his thesis research in Zev Bryant, Ph.D.’s lab at Stanford University Kevin Aris examined how DNA supercoiling affects the energetics of DNA-protein interactions. He showed that DNA shape, or topology, affects how genes can be edited by different mechanisms. Specifically, Aris demonstrated that DNA supercoiling imparts physical reasons for why enzymes, such as Cas9 and Cas12a, naturally differ in how they bind to their DNA target.

As a Robertson Foundation – Jane Coffin Childs Fellow in Aaron Streets’ lab at UC Berkeley, Aris will use his expertise in the CRISPR-Cas gene editing system not just to edit genes, but as a tool to measure DNA supercoiling across the genome in living cells. His goal is to build a genome-wide map of DNA shape to understand how it affects binding by gene regulators (like transcription factors). In addition to providing fundamental new knowledge about DNA shape in cells and gene regulation, Aris will investigate if and how this parameter is impacted in diseases such as cancer.

Neali A. Armstrong, Ph.D. Jane Coffin Childs Fellow

Columbia University

Project Title: Simultaneous measurement of AMPA receptor structure and function

Donna J. Arndt-Jovin, Ph.D. Jane Coffin Childs Fellow

Stanford University

Project Title: Isoleucyl transfer ribonucleic acid synthetase

Tal I. Arnon, Ph.D. Jane Coffin Childs Fellow

California Institute of Technology

Project Title: Structure and function of the NKp30 killer receptor

Amjad Askary, Ph.D. Jane Coffin Childs - HHMI Fellow

California Institute of Technology

Project Title: Dynamics of cell state transitions in early mammalian development

Strong 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 ‚Äúwriting‚Äù 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.

Meenakshi J. Asokan, Ph.D. Jane Coffin Childs Fellow

Princeton University

Project Title: Hormone-mediated changes in neural computations that drive flexible social behaviors

Social interactions and behaviors are mediated by a hormone-sensitive brain network. For example, female mice are sexually receptive only during a certain phase of their estrous cycle around ovulation. Yet, it is still unclear how hormones modulate this network’s circuit architecture and dynamics to dictate changes in behavior.

Dr. Meenakshi Asokan will examine this missing link in Dr. Annegret Falkner’s lab at Princeton University. Dr. Asokan hypothesizes that sex hormones reorganize neural dynamics and functional coupling in crucial hubs for top-down control of sociability to drive flexible female social choice. Asokan will use a behavioral assay and computational tools to quantify the hormone-dependent changes in social motivation and preference. She will then pinpoint the location of these differences in the brain, address how these neural ensembles alter the coding of social interactions and manipulate these regions to verify their causal role in hormone-dependent changes in social behaviors. These studies will provide fundamental insight into how sex hormones rewire information processing to impact social behaviors. This information will be invaluable in situations where steep changes in hormone levels are linked to depressive symptoms such as during post-partum, perimenopausal, and pre-menstrual stages in women.

Asokan built her expertise in understanding how neural circuits influence perception and behaviors in Dr. Daniel Polley’s lab at Harvard University. During her graduate studies, Asokan focused on neural substrates that underlie changes in perception following noise-induced hearing loss. She localized this change to layer 5 cortico-collicular axons that innervate the amygdala and striatum, which explains the exacerbated sound-triggered anxiety and aversiveness in hearing loss patients. Additionally, through multi-regional extracellular recordings and optical measurements, Asokan discovered cooperative plasticity in inputs to amygdala as mice learn to reappraise neutral stimuli as possible threats. Asokan will now use her expertise in linking brain regions to changes in social behavior to investigate how sex hormones influence these processes during her postdoctoral research.

Manfred Auer, Ph.D. Jane Coffin Childs Fellow

New York University

Project Title: Electron tomography of hair cell stereocilia

Judith A. Austin, Ph.D. Jane Coffin Childs Fellow

University of California, San Francisco

Project Title: Analysis of regulation of steroid receptor activity

Gad Avigad, Ph.D. Jane Coffin Childs Fellow

New York University

Project Title: Carbohydrate metabolism of bacteria

Erika A. Bach, Ph.D. Jane Coffin Childs Fellow

Harvard Medical School

Project Title: Characterization of the Drosophila unpaired receptor

Minwoo Bae, Ph.D. Robertson Foundation-Jane Coffin Childs Fellow

Yale University

Project Title: De Novo Designed Trojan-Horse Protein Antibiotics Against Gram-Negative Bacteria

Minwoo Bae, Ph.D., believes microbes contain a huge, largely unexplored supply of proteins that can be discovered and engineered for new medical and biotech uses. His past work found microbial proteins with unusual functions. Now, as a Robertson Foundation – Jane Coffin Childs Fellow, he plans to build “Trojan-horse” delivery systems inspired by microbial toxins that can smuggle next-generation antibiotics into bacteria.

As a graduate student in Emily Balskus’s lab at Harvard, Bae identified gut microbial enzymes that break down dietary polyphenols. He first found an enzyme that metabolizes hydrocaffeic acid abundant in coffee, and later discovered multiple enzymes that convert ellagic acid into urolithin A, a compound linked to anti-aging and anti-inflammatory effects. This work helps explain how the gut microbiome changes the chemistry of what we eat and shows that microbes have evolved proteins that can carry out rare, complex chemical reactions.

Because many clever microbial tools come from bacteria competing with each other, Bae joined Joseph Mougous’s lab at Yale to study and repurpose these systems. Antibiotic resistance is a major global health challenge, including for Gram-negative pathogens whose outer membranes are an impenetrable fortress keeping antibiotics out. His goal is to engineer microbial protein toxins that can pass through outer-membrane transporters, enabling antibiotics to be brought inside “by deception.” He’s especially interested in a pathogen associated with colorectal cancer, and his work could support both new antibiotic development and potential new strategies related to colorectal cancer.

Inhwa Baek, Ph.D. Jane Coffin Childs Fellow

Rockefeller University

Project Title: Investigating the roles of spatiotemporal genome architecture in malignancy

Profound alterations in gene expression profiles occur as stem cells from normal tissue transform into cancer stem cells (or tumor-initiating cells) that are able to initiate tumor growth and propagate tumor masses. However, how the gene expression program is rewired during tumorigenesis remains elusive. My research project centers on exploring and identifying key factors that are responsible for driving the divergence of their gene expression profiles. Using in vivo mouse models and genomics and imaging approaches, I am investigating how spatiotemporal genome organization plays a role in oncogenic transcriptional reprogramming during skin squamous cell carcinoma (SCC) development. Skin SCC has emerged as a public health issue due to its increasing incidence and potential for metastasis and recurrence, particularly for the patients placed on immunosuppressive drugs. If successful, my work would further our understanding of the mechanisms underlying oncogenic transcriptional reprogramming and provide new avenues for developing new cancer therapeutics.

Ling Bai, Ph.D. Jane Coffin Childs Fellow

University of California, San Francisco

Project Title: Identification of homeostatic signals that regulate AgRP "hunger" neurons

AgRP neurons in the arcuate nucleus of hypothalamus are exposed to plasma circulating signals and playing critical role in the regulation of feeding and homeostasis. Recently, real-time measurements of AgRP neuron activity in awake mice have revealed an unexpected rapid inhibition of these neurons by the detection and ingestion of food. These results challenge the current model for homeostatic regulation, in which AgRP neurons simply monitor circulating hormonal and nutritional signals to regulate feeding, begging the question of what physiological signals regulate AgRP neurons‚Äô activity and generate hunger.

I propose to identify this fundamental ‚Äúhunger signal‚Äù that regulates AgRP neurons through systematic experiments that combine in vivo recording with surgical, pharmacologic, genetic, and optical manipulations. I will reexamine the contribution of traditional hormonal signals, and characterize the function of different postprandial gastrointestinal stimuli in regulating AgRP neuron activity. Next, I will further identify the underlying mechanisms by examining the contribution of gastrointestinal sensory inputs as well as circulating nutrients. Together, these will aid in understanding the regulation of AgRP neuron activity and hunger, which provides a basis for the understanding of obesity as well as diverse motivated behaviors.

Jihong Bai, Ph.D. Jane Coffin Childs Fellow

Massachusetts General Hospital

Project Title: Molecular basis of synapse elimination in C elegans

Julie C. Baker, Ph.D. Jane Coffin Childs Fellow

University of California, Berkeley

Project Title: Expression cloning of murine inducing factors

Timothy S. Baker, Ph.D. Jane Coffin Childs Fellow

Medical Research Council (MRC),UKRI /
Cambridge University

Project Title: Electron Microscopy

Christa A. Baker, Ph.D. Jane Coffin Childs Fellow

Princeton University

Project Title: Auditory coding contributing to drosophila courtship behavior

Steven A. Baker, M.D., Ph.D. Jane Coffin Childs Fellow

Stanford University

Project Title: A comparative genomic analysis of lifespan evolution in vertebrates

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.