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Tracy Young-Pearse, Ph.D.

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Overview
Young-Pearse lab website:
http://youngpearselab.bwh.harvard.edu/Young-Pearse_Lab/home.html

Mentoring
Available: 01/10/22, Expires: 01/01/27

A central question in Alzheimers Disease (AD) is the role of cell type-specific changes associated with the onset and progression of the disease. Genome-wide association studies have identified genes linked to AD, and recent large-scale transcriptomic and proteomic studies of post-mortem brain tissue have highlighted candidate genes and proteins with significant associations to pathological and clinical manifestations of AD. Together, these genetic and molecular studies have implicated neurons, astrocytes, and microglia as key players in AD pathogenesis and cognitive decline. However, these genetic and post-mortem profiling studies cannot resolve the degree to which a change in cell type expression profile is cell autonomous, as opposed to being a downstream effect of changes in other cell types. To tackle this question, we propose an innovative mixed in vitro co-culture approach to understand the effects of cell types from donors with variations in AD pathology and or AD dementia on cell types derived from individuals with or without cognitive decline or pathology. We use induced pluripotent stem cell (iPSC) lines from members of the Religious Order Study/Memory and Aging Project (ROSMAP), for whom we have detailed pathological, clinical, whole- genome sequencing, and post-mortem molecular data. This allows us to anchor our in vitro findings directly to patient phenotypes and analyses of post-mortem brain tissue data. Based on this anchoring, our approach is to mix and match cell type-specific cultures from different iPSC lines, thereby allowing us to disentangle which cell type-specific changes in vitro are likely cell type autonomous, and which are induced non- autonomously by cells from a donor with a different genetic background, pathology, and ante-mortem cognitive trajectory. Importantly, we look for conserved, polygenic AD-associated signals in vitro that are present across donors with varied genetic backgrounds, as opposed to directly characterizing the effect of a specific variant on cell type. Given the highly multifactorial nature of AD genetic risk variants, we believe this approach allows for robust identification of convergent cell type-specific effects associated with the disease. Students may be involved with either the "wet lab" generation of data, the "dry lab" analysis of data, or a combination of both. The specific goals of the individual's project will depend upon the status of the overarching project on the start date.


Research
The research activities and funding listed below are automatically derived from NIH ExPORTER and other sources, which might result in incorrect or missing items. Faculty can login to make corrections and additions.
  1. RF1NS117446 (YOUNG-PEARSE, TRACY L) Sep 15, 2020 - Aug 31, 2024
    NIH
    Cell and Molecular Consequences of Alzheimer's Disease Genetic Variants on BBB Integrity and Function
    Role: Principal Investigator
  2. R21MH118576 (YOUNG-PEARSE, TRACY L) Apr 1, 2019 - Feb 28, 2021
    NIH
    Establishing a human cellular model of sex differences in the brain
    Role: Principal Investigator
  3. R01AG055909 (YOUNG-PEARSE, TRACY L) Jul 15, 2018 - May 31, 2023
    NIH
    Probing Heterogeneity of Alzheimer's disease using iPSCs
    Role: Principal Investigator
  4. RF1AG057457 (CHANG, RUI) Sep 15, 2017 - Aug 31, 2021
    NIH
    Building Novel Predictive Networks for high-throughput, in-silico Key Driver Prioritization to Enhance Drug Target Discovery in AMP-AD and M2OVE-AD
    Role: Co-Principal Investigator
  5. R21AG056011 (YOUNG-PEARSE, TRACY L) Apr 1, 2017 - Mar 31, 2019
    NIH
    Feasibility of studying vulnerability versus protection to high amyloid load using iPSCs
    Role: Principal Investigator

Bibliographic
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Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.