University of California, Santa Barbara
Appointed in 1983
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University of California, Santa Barbara
Appointed in 1983
Beatson Institute for Cancer Research, Scotland
Appointed in 1970
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Beatson Institute for Cancer Research, Scotland
Appointed in 1970
University of California, San Francisco
Appointed in 2003
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University of California, San Francisco
Appointed in 2003
Harvard University Medical School
Appointed in 2020
California Institute of Technology
Appointed in 1958
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California Institute of Technology
Appointed in 1958
Harvard University Medical School
Appointed in 2005
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Harvard University Medical School
Appointed in 2005
Stanford University School of Medicine
Appointed in 2006
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Stanford University School of Medicine
Appointed in 2006
University of California, San Francisco
Appointed in 2017
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University of California, San Francisco
Appointed in 2017
Stanford University School of Medicine
Appointed in 2013
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Stanford University School of Medicine
Appointed in 2013
During my Ph.D. studies at Washington University, I worked with David Holtzman to show that ApoE e4 may increase Alzheimer’s disease risk by impairing Ab clearance from the brain, thus shifting the onset of its accumulation. My interest in neurodegeneration and aging motivated me to understand factors that regulate aging and brain health in unconventional ways. My project as a Jane Coffin Childs fellow in Tony Wyss-Coray’s laboratory has been to elucidate a novel systemic-neurogenic communication mechanism that appears to be disrupted in the context of brain irradiation therapy. Specifically, I am investigating the role of immune signaling molecules in mediating the neurogenic and cognitive dysfunction observed in the post-irradiation syndrome in pediatric brain cancer patients. Additionally, I am actively pursuing whether related blood-borne signaling molecules in young plasma may be sufficient to ameliorate age-related decreases in cognition and synaptic plasticity. To examine these complex mechanisms, I am leveraging various physiological methods, including plasma transfer and parabiosis.
Yale University /
University of California, Berkeley
Appointed in 1974
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Yale University / University of California, Berkeley
Appointed in 1974
University of California, San Francisco
Appointed in 2021
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University of California, San Francisco
Appointed in 2021
Infertility represents a significant societal burden, as nearly 60% of human pregnancies fail before the embryo implants into the uterus. These miscarriages become more prevalent as women age above 35 years. But implantation remains a black box within development because it occurs within the mother’s body, so progress revealing its physical mechanisms is lagging. Early in preimplantation sages, primitive placental lineages must be specified for faithful implantation. Driving these lineage commitments are subcellular mechanical forces that transduce expression of downstream fate determinants for specification and ultimate invasion of placental tissues. However, in mammalian embryos of aged mothers, embryos display poor developmental health with decreased placental structures owing to impaired implantation. We hypothesize that these pathologies may stem from either early defects in tissue specification or later mechanical uterine invasion, both of which could give rise to age-related spontaneous abortions. This proposal therefore seeks to understand how the early cell biological and biophysical mechanisms are altered in the embryo with advanced maternal age, and how these mechanisms can be tuned to rejuvenate “aged” embryos to rescue developmental potential. Working in embryos of aged mice, we will combine approaches from cell and developmental biology, biophysics, and synthetic biology to ask: (1) Does maternal aging decouple the embryo’s upstream mechanics from downstream signal transduction during placental fate acquisition? (2) Is the logic of signal transduction for placental fate determinants altered via maternal aging? and (3) Do these age-related mechanisms together promote defective mechanical invasion during uterine implantation? Bridging these disparate scientific spheres will be critical in understanding infertility and improving female reproductive longevity.
University of California, Los Angeles
Appointed in 2003
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University of California, Los Angeles
Appointed in 2003
Harvard University
Appointed in 1975
Massachusetts Institute of Technology
Appointed in 1982
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Massachusetts Institute of Technology
Appointed in 1982
Duke University
Appointed in 1992
University of California, Berkeley
Appointed in 2001
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University of California, Berkeley
Appointed in 2001
Harvard University
Appointed in 2006
Salk Institute for Biological Studies
Appointed in 1994
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Salk Institute for Biological Studies
Appointed in 1994
Universite de Paris, France
Appointed in 1971
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Universite de Paris, France
Appointed in 1971
Massachusetts Institute of Technology
Appointed in 1982
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Massachusetts Institute of Technology
Appointed in 1982
Insitut for Biochemie, Max-Planck-Institut
Appointed in 1959
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Insitut for Biochemie, Max-Planck-Institut
Appointed in 1959
University of Washington, Seattle
Appointed in 1974
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University of Washington, Seattle
Appointed in 1974
Whitehead Institute for Biomedical Research
Appointed in 1996
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Whitehead Institute for Biomedical Research
Appointed in 1996
Harvard University
Appointed in 2021
How animal brains evolved the capacity for sophisticated computation is not well understood. One major facet of this problem is the evolution of chemosensation. Chemosensation is the primary sense of most animals, and involves complex neural computations. We do not know how this sense evolved, or how most animals – which are aquatic invertebrates – perform chemosensation. I am studying chemosensation in an acoel worm, an aquatic invertebrate that by virtue of its phylogenetic position as the likely outgroup to all other animals with central nervous systems, retains some primitive features of early central nervous systems. Acoels nonetheless perform sophisticated behavior that requires complex chemosensory processing, but how their brains and chemosensors work is unknown. Using a combination of automated behavioral tracking, transgenics, and neural activity imaging, I aim to understand the logic of chemosensory processing in a tractable acoel worm. Through comparisons with known chemosensory mechanisms of other animals, this will shed light on how complex chemosensory systems evolved. This project will also establish experimental approaches for the future study of neural computations and behavior in acoel worms and other aquatic invertebrates.
Massachusetts Institute of Technology
Appointed in 2002
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Massachusetts Institute of Technology
Appointed in 2002
University of California, Berkeley
Appointed in 2005
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University of California, Berkeley
Appointed in 2005
Yale University
Appointed in 2011
Harvard University Medical School
Appointed in 2012
Harvard University
Appointed in 1982
Carnegie Institute for Science
Appointed in 1991
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Carnegie Institute for Science
Appointed in 1991
Whitehead Institute for Biomedical Research
Appointed in 1987
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Whitehead Institute for Biomedical Research
Appointed in 1987
Centre Nationale de la Recherche Scientifique, France
Appointed in 1966
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Centre Nationale de la Recherche Scientifique, France
Appointed in 1966
University of California, San Diego
Appointed in 2003
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University of California, San Diego
Appointed in 2003
Michigan State University
Appointed in 1965
Rockefeller University
Appointed in 1972
Scripps Research Institute
Appointed in 1989
Harvard University
Appointed in 2005
Stanford University
Appointed in 2007
Harvard University Medical School
Appointed in 2012
Harvard University Medical School
Appointed in 2014
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Harvard University Medical School
Appointed in 2014
Dana-Farber Cancer Institute
Appointed in 2015
My current research focuses on the molecular mechanisms underlying adipose tissue development and metabolism. In particular, I use genetic and biochemical approaches to identify the molecular differences between the energy-storing white fat and energy-dissipating brown/beige fat in the hope of using those differences to help design therapeutic strategies for the prevention and treatment of obesity._x000D_
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Brown and beige fat dissipates energy as heat in a process known as non-shivering thermogenesis. The transcriptional regulator Prdm16 was previously identified to facilitate thermogenesis; however, its relevant target genes remain incompletely known. Through ChIP-Seq and RNA-Seq, we have identified a number of potential Prdm16 targets. Among those, I focus on delineating the functions of a rectifying potassium channel Kcnk3 in thermogenesis. Kcnk3 is known to set the plasma membrane potential by generating potassium currents in neurons. I hypothesize that Kcnk3 sets the appropriate membrane potential in thermogenic adipocytes, which may be important for thermogenesis. I will test this hypothesis using fat-specific Kcnk3 knockout mice.
University of California, San Francisco
Appointed in 2015
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University of California, San Francisco
Appointed in 2015
Stanford University
Appointed in 2016
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.
University of California, San Francisco
Appointed in 2016
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University of California, San Francisco
Appointed in 2016
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.
Stanford University
Appointed in 2020
Reproductive aging is a global challenge. Older men and women face fertility loss and a higher chance of having children with genetic disorders. Currently, we lack a detailed molecular understanding of what causes reproductive aging in vertebrates. I am developing an emerging short-lived model system, the African killifish, to study vertebrate reproductive aging. The lifespan of this organism is 4 times shorter than mice and 7 times shorter than zebrafish. I will combine my graduate training (gamete biology) with the expertise of the Brunet Lab (killifish and aging) to probe the molecular basis of age-dependent fertility decline in the killifish and identify potential targets for therapeutic intervention. These studies will shed light on methods to protect or rejuvenate the germline from aging, which can have a profound impact on human fertility.
Rockefeller University
Appointed in 1978
New York University, Grossman School of Medicine
Appointed in 2021
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New York University, Grossman School of Medicine
Appointed in 2021
Mycobacterium tuberculosis, the causative agent of tuberculosis, is one of the leading causes of death due to infectious disease. Mtb establishes a replicative niche within the phagosomal compartment of host macrophages where it siphons nutrients from the host cell for its survival. To thrive within this hostile environment, Mtb has evolved a complex, protective cell envelope along with an ensemble of active transporters to import nutrients across this nearly impermeable barrier. The Mammalian Cell Entry (MCE) proteins have been implicated in nutrient transport as well as outer membrane maintenance and are important virulence factors in Mtb. However, the molecular bases for these functions are not known and the MCE proteins could play additional roles in the cell that have yet to be characterized. Therefore, I am currently determining the first structures of the mycobacterial MCE proteins and their associated factors using a combination of endogenous purification strategies and cryo-electron microscopy (cryo-EM), and developing in vivo assays to monitor MCE substrate binding and transport. This work will provide structural and mechanistic insights into these important virulence factors, which are potential targets for drug development.
University of California, San Diego
Appointed in 2023
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University of California, San Diego
Appointed in 2023
Mutations in LRRK2, a multi-domain kinase and GTPase, is the most frequent cause of familial Parkinson’s disease. However, we currently lack the detailed understanding of LRRK2 function that could lead to therapeutics for Parkinson’s. Dr. Siyu Chen will use cryo-EM and cryo-ET to study LRRK2 and its mutants in biochemical reconstitutions and in cells. Dr. Chen will conduct these experiments in Dr. Elizabeth Villa’s lab at the University of California, San Diego. These experiments will directly visualize the molecular mechanisms of LRRK2 and interacting partners’ function in the cell, and how pathogenic mutations disrupt these processes. Therefore, Dr. Chen’s research may inform on novel therapies for Parkinson’s disease.
As a graduate student in Dr. Yuan He’s lab at Northwestern University, Chen studied DNA double-strand break repair. Specifically, Dr. Chen used Cryo-EM to solve two key intermediate states in the non-homologous end-joining pathway (NHEJ). These structures revealed novel interaction surfaces between NHEJ proteins and allowed Dr. Chen to propose a near complete reaction cycle for NHEJ. Dr. Chen will now apply his cryo-EM expertise to LRRK2 and will use cryo-ET to visualize LRRK2 in cells.
University of Washington
Appointed in 2022
Internal brain states greatly influence our sensations and perception of the external world. Incidents such as stress, hunger, thirst, and pregnancy have all been described as inducing different ‘brain states’ within individuals, altering basic neural properties such as sensory perception, memory, interception, and attention. However, we do not understand how our brains dynamically shape our perceptions and behaviors during state shifts. Here we aimed to create stable brain state models by exposing animals to either chronic social isolation or exercise, two opposing types of behavioral intervention to represent positive and negative experiences. By measuring multi-domain behavioral profiles across the brain during long-term social isolation or exercise, we tested if these biological fingerprints can predict animals’ brain states. To further dissect the neuromodulation changes during brain state shifts, we focused first on the locus coeruleus (LC). LC both receives and sends broad projections throughout the brain. LC cells could then mediate brain-wide changes through its noradrenergic population to control arousal, attention, and sensory perceptions. When simultaneously imaging LCDBH cell body and terminal activities across multiple brain regions, we observed different activity patterns when mice were presented with a diverse array of stimuli. We have also observed dynamic single-cell activities toward different sensory cues, which further confirms the heterogeneity within the LCDBH population. By combing in vivo imaging, circuitry mapping, and biochemical detection, we aim to examine the neuromodulatory signaling dynamics in and out of LC during brain state shifts induced by long-term exercise and social isolation.
University of Cambridge, England /
Harvard University
Appointed in 1973
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University of Cambridge, England / Harvard University
Appointed in 1973
University of California, San Francisco
Appointed in 1994
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University of California, San Francisco
Appointed in 1994