| 2006 — 2009 |
Rexach, Jessica E |
F31Activity Code Description:
To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
The Story of Methyl-Cpg Binding Protein 2 Glycosylation @ University of California Los Angeles
[unreadable] DESCRIPTION (provided by applicant): We have recently discovered the activity-dependent, intracellular O-GlcNAcylation of MeCP2 in embryonic cortical neurons. This research proposal aims to 1) identify which amino acids of MeCP2 are O- GlcNAcylated and 2) determine the functional significance of O-GlcNAc-MeCP2. We hypothesize that following seizure, MeCP2 O-GlcNAcylation triggers the dissociation of MeCP2 from certain gene promoters it is involved in repressing, thereby triggering the expression of those genes. This finding will further the understanding of the molecular mechanisms governing Rett syndrome, a common form of female mental retardation that is characterized by postnatal onset and seizures, and caused by loss of MeCP2 function. [unreadable] [unreadable] [unreadable]
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| 2019 — 2021 |
Rexach, Jessica E |
K08Activity Code Description:
To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Single Cell and Tissue Level Functional Genomic Analysis of Astrocyte-Related Mechanisms in Tauopathy @ University of California Los Angeles
ABSTRACT Genetic evidence indicates that glia, including microglia and astrocytes, play causal roles in Alzheimer?s disease. Therefore, detailed mechanistic understanding of causal glial factors has strong potential to lead to new therapies. However, little is known about neuronal-glial interactions and how emerging pictures of glial heterogeneity and changing states over time contribute to disease. This proposal aims to define astrocyte subtypes and states present across the spectrum of disease pathology in human neurodegenerative tauopathies, and identify key regulatory factors with which to experimentally manipulate these subtypes and states for mechanistic study, via three specific aims. First, through analyzing a unique single nuclear sequencing dataset to identify diverse astrocyte subtypes and states present across a spectrum of tau pathology and neurodegeneration, and integrating these data with other whole tissue and single cell datasets to identify reproducible findings and observe relationships to other cell types. Second, by identifying and validating key molecular regulators of disease-associated astrocyte subtypes and states by combining bioinformatics predictions with experimental testing in human iPSC models. Third, by assessing the functional relationship between specific astrocytes subtypes and states and neurodegeneration in vivo using mouse models of neurodegeneration. By including both human post-mortem data, experimental human in vitro systems, and mouse in vivo systems, I will focus on robust and reproducible findings that are amenable to detailed functional and mechanistic study. Ensuring the success of this project is a rich institutional environment and mentorship team of world-class leaders in single-cell sequencing, basic astrocyte biology, functional genomics, and experimental disease modeling. The training aspects of this proposal complement a strong background in molecular biology and biochemistry with a solid foundation in genomics and bioinformatics as well as astroglial biology. Altogether, the proposed work completes a professional transition to independent investigator focused on glial mechanisms of neurodegeneration, by establishing the necessary experience and publication record in the integration of functional genomics and single-nuclear sequencing with experimental glia biology.
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