Project 4: Cross-species Dissection of Cellular Response to APOE Genotype and AD Pathology Using Single-cell Multi-omics

Information

  • Research Project
  • 10271129
  • ApplicationId
    10271129
  • Core Project Number
    P01AG073082
  • Full Project Number
    1P01AG073082-01
  • Serial Number
    073082
  • FOA Number
    PAR-19-314
  • Sub Project Id
    6453
  • Project Start Date
    8/15/2021 - 2 years ago
  • Project End Date
    7/31/2026 - 2 years from now
  • Program Officer Name
  • Budget Start Date
    7/1/2021 - 2 years ago
  • Budget End Date
    6/30/2022 - a year ago
  • Fiscal Year
    2021
  • Support Year
    01
  • Suffix
  • Award Notice Date
    8/4/2021 - 2 years ago

Project 4: Cross-species Dissection of Cellular Response to APOE Genotype and AD Pathology Using Single-cell Multi-omics

PROJECT 4 ? SUMMARY Alzheimer?s disease (AD) is driven by a complex, multifactorial etiology that has stymied progress toward effective therapies. Despite decades of research on amyloid-beta (A?) and tau, we do not fully understand the cellular and molecular effects of these key disease drivers. These pathologic proteins interact with genetic drivers, such as apolipoprotein E4 (APOE4), creating complex and diverse cellular and brain-regional effects. One promising approach to understanding the diverse effectors of AD pathogenesis is to study central processes that are perturbed by each disease driver. Both AD pathology and APOE genotype exacerbate neural network dysfunction in brain regions critical for cognition, nominating neural network function as one such critical central process. Besides causing AD-related cognitive decline, neural network dysfunction results in comorbidities such as subclinical epileptiform activity. The lack of a comprehensive picture of the cellular, molecular, and genetic underpinnings of AD underscores the need for detailed and rigorous dissection of the many factors that contribute to this disease. The goal of this PPG is to identify the cellular and molecular consequences of the interactions between A?, tau, and APOE and determine how they lead to prolonged neural network dysfunction. Genetic and pathologic alterations drive AD by affecting cellular state. For example, neuronal and glial cells interact with and are affected by A? and tau pathology, leading to changes in gene expression that are further altered by the genetic milieu of the cell, culminating in an altered cellular state. Understanding how cellular state changes and is controlled by multifactorial inputs of AD could lead to novel therapeutic strategies. However, these cellular responses are cell type? and cell context?specific. Techniques for single-cell transcriptomic and epigenomic profiling now make it possible to characterize the specific cellular response to combinatorial interactions between A?, tau, and APOE. To systematically understand cellular responses to A?, tau, and APOE in human AD, Project 4 will comprehensively characterize cell-type-specific transcriptomics and epigenomics in primary human samples. In Aim 1, we will perform single-nucleus (sn) transcriptomic and epigenomic profiling in human cohorts that have been rigorously characterized, both clinically and pathologically, and that vary in APOE genotype, A? and tau pathology, and cognitive state. In Aim 2, we will integrate these data with snRNA-seq results from novel humanized mouse lines designed to dissect the combinatorial effects of A?, tau, and APOE (with Projects 1?3). In Aim 3, we will use single-cell technologies to understand the effects of therapeutic reversal of prolonged neural network dysfunction in mouse models (with Projects 2 and 3). The results of the proposed studies, in concert with the other complementary projects, will provide an unparalleled characterization of the multifactorial etiology of neural network dysfunction in AD, and may suggest novel avenues for therapeutic intervention.

IC Name
NATIONAL INSTITUTE ON AGING
  • Activity
    P01
  • Administering IC
    AG
  • Application Type
    1
  • Direct Cost Amount
    518083
  • Indirect Cost Amount
    447641
  • Total Cost
  • Sub Project Total Cost
    965724
  • ARRA Funded
    False
  • CFDA Code
  • Ed Inst. Type
  • Funding ICs
    NIA:965724\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    ZAG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    J. DAVID GLADSTONE INSTITUTES
  • Organization Department
  • Organization DUNS
    099992430
  • Organization City
    SAN FRANCISCO
  • Organization State
    CA
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    941582261
  • Organization District
    UNITED STATES