Environmental Biosensors in the Oligodendrocyte Lineage
Funded by National Institute of Neurological Disorders and Stroke, Award # R35NS111604
Project Summary Myelinating glial function is fundamental for brain health and its impairment is detected in a growing number of psychiatric and neurological disorders. Studying the basic mechanisms regulating the progression of progenitors into myelinating oligodendrocytes in the developing and adult brain therefore has substantial implications for a better understanding of the mechanisms regulating proper brain function, while informing on potential causes for dysfunction, and providing the framework for the design of novel therapeutic strategies. Our lab has pioneered the concept of epigenetic regulation of oligodendrocyte progenitor differentiation. We identified DNA and histone changes responsible for repression of gene expression during developmental myelination and in adult remyelination, identified the responsible enzymes and defined their functional significance using transgenic mice, characterized them in the context of neuropathology and evaluated translational implications. We also reported impaired epigenetic regulation of oligodendrocyte differentiation in aging, in animal models of depression and in post-mortem Multiple Sclerosis human brains. We collaborated with chemical engineers to develop compounds with the ability to reverse some of the epigenetic changes. We also made unanticipated discoveries on the cross-talk between gut metabolites, social experiences, mechanical stimuli and myelination. In broad terms our objective is to understand the mechanisms that allow the chemical, metabolic and physical environment to induce a biological response in progenitor cells and result in the formation of myelin, proliferation and transformation of persistence of an undifferentiated state in the developing and adult brain. Our ultimate goal is to decipher the signals driving the differentiation of progenitors into myelinating glia, in order to inform on the design of regenerative strategies. In this application we propose an interdisciplinary approach, which includes the integration of several disciplines to develop new tools and experimental approaches for the discovery of novel modalities of signal transduction. We propose to use cell biology, biophysics, advanced imaging spectroscopy, nanotechnology and super resolution microscopy and new transgenic lines, epigenomic and proteomic approaches to addresses key open questions in the field. The proposed studies will develop new concepts and set the foundation on how progenitors interpret specific metabolic signals, mechanical forces, neuronal activity to regulate brain function. We expect that the results of the proposed experimental plan will set the stage for the development of novel therapeutic strategies for several neurological and psychiatric disorders, while advancing current knowledge of brain development and myelin formation.
Architecture, dynamics and cell-specific behavior of tau condensates
Funded by National Institute on Aging, Award # R01AG082250 (Co-Investigator)
Project Summary The ultimate goal of this proposal is to understand the molecular and cellular substrates of early tau pathology, in order to create the foundation for future therapeutic targets for Alzheimer’s Disease (AD) and Alzheimer’s Disease Related Dementias (ADRD). Tau is a protein, expressed in neurons and oligodendroglial cells, whose aggregation is a pathological hallmark of a wide range of neurodegenerative diseases, including Fronto-Temporal-Dementia (FTD). Mounting evidence shows that the pathogenic process begins long before the detection of neuronal aggregates, with the detection of white matter changes in subjects with mild cognitive impairment, although the underlying pathogenic processes responsible for these changes remain only partially understood. This proposal will directly address this major gap of knowledge in the field, and tackle the major research priority of the 2019 NIH ADRD Summit, to investigate the early events of the disease. We leverage the expertise of the PI in biochemistry and phase separation and that of the co-I in myelin biology, to test the hypothesis that the white matter changes detected at the early stages of ADRD are mediated by misregulation of the condensed state of tau in oligodendrocytes. This hypothesis is motivated by the evidence that: 1) tau can self-assemble into a novel phase-separated condensed state (“condensate”); 2) tau mutations specific for FTD specifically impact tau condensates and 3) that oligodendroglial lineage cells, the myelin-forming cells of the central nervous system, are specific sites of tau-mediated dysfunction at the early stages of the neurodegenerative process. Extensive evidence in human subjects and animal models of FTD identify myelin damage and oligodendroglial dysfunction at the earliest stages of cognitive decline and support a model of neurodegeneration consequent to myelin pathology and occurring long before the detection of aggregates. Here we take an interdisciplinary biophysical and cellular approach that leverages expertise in tau biochemistry and glial biology, in order to test this hypothesis. In aim1 we will develop quantitative metrics for defining tau condensates – a crucial advance necessary for understanding how tau condensates are modulated. In aim 2 we will determine the influence of tau pathological variants and myelin protein and lipids on tau condensate properties. In aim 3 we shall examine the role of endogenously expressed and exogenously uptaken tau and tau variants in oligodendrocyte lineage cells at specific stages of differentiation. Together, results from this work will illuminate the role of tau condensates in oligodendrocytes and further our knowledge of the events occurring at the early stages of tau pathology.
Effects of music intervention on anxiety in CUNY student population and underlying mechanisms
Funded by The City University of New York Planning Grant
The emerging mental health crisis in the US, disproportionally affects the diverse CUNY student body. COVID-related isolation, financial stability concerns, and global conflicts such as climate crisis and war, contribute to raising levels of stress and anxiety. Yet, access and stigmas related to mental health, challenge our student communities, as witnessed by the Directors of Mental Health Counseling centers at most CUNY colleges. The goal of this proposal is to create a team of CUNY-wide faculty, addressing this challenge by applying for external funds.