New Down syndrome brain organization revealed by single-cell genomics

Information

  • Research Project
  • 10471627
  • ApplicationId
    10471627
  • Core Project Number
    R56AG073965
  • Full Project Number
    1R56AG073965-01
  • Serial Number
    073965
  • FOA Number
    RFA-OD-20-005
  • Sub Project Id
  • Project Start Date
    9/15/2021 - 2 years ago
  • Project End Date
    6/30/2023 - 11 months ago
  • Program Officer Name
    PETANCESKA, SUZANA
  • Budget Start Date
    9/15/2021 - 2 years ago
  • Budget End Date
    6/30/2022 - a year ago
  • Fiscal Year
    2021
  • Support Year
    01
  • Suffix
  • Award Notice Date
    9/9/2021 - 2 years ago

New Down syndrome brain organization revealed by single-cell genomics

PROJECT SUMMARY/ABSTRACT Nearly 100% of Down syndrome (DS; trisomy of human chromosome 21) individuals that live into their 5th decade of life and beyond, show Alzheimer?s disease (AD)-like dementia and neuropathology (DS-AD), representing a prominent DS comorbidity that has recently been reported as the leading cause of death for DS adults. Beyond trisomy of chromosome 21, which includes the key AD gene, amyloid precursor protein (APP), the molecular mechanisms underlying DS-AD have resisted identification. There are no disease-modifying therapies (DMTs) to prevent or treat DS-AD, which could improve DS quality of life and lifespan. This INCLUDE proposal will transform our understanding of DS by revealing the transcriptomic (RNA) and genomic (DNA) single-cell landscape of the aging DS individual, and especially the DS-AD brain, by centering upon a novel human brain molecular mechanism that might underlie DS-AD: somatic gene recombination (SGR) and resultant genomic and transcriptomic heterogeneity. SGR has the potential to change the DNA blueprint of DS brain cells resulting in functional consequences for brain cells that could explain DS-AD onset as well as other DS brain comorbidities such as autism and epilepsy. SGR has not been examined in DS brains, which if operational, would provide a fundamentally new view on how genes and gene dosage act to promote DS-AD over time. SGR is known to act on APP in normal and sporadic AD neurons, resulting in thousands of new APP variants within individual human brains and has been independently confirmed in the scientific literature. The proven increases in DS brain gene expression, combined with the identified linkage of gene expression to SGR, implicates genes transcriptionally increased by trisomy 21 as new targets for SGR in DS-AD. APP is likely the ?tip of the iceberg? for DS-affected genes in neurons and non-neuronal cells, with implications for both DS as well as other states of the normal and diseased human brain. Three independent, but deeply-connected, Research Elements (REs) will be completed by a proven, collaborative team of molecular biologists, neuroscientists, neurologists, bioengineers, and bioinformaticians to test the hypothesis that SGR contributes to DS brain deficits and DS-AD by altering known and unknown disease genes at the single-cell transcriptomic and genomic level within the DS brain. RE1 and RE2 will use cutting-edge sequencing technologies to interrogate the transcriptomic and genomic heterogeneity of single nuclei from DS and DS-AD brains compared to controls, and will informatically integrate transcriptomic expression, chromatin accessibility, novel isoform detection and genomic mosaicism forms, including gencDNAs, within single cells across cell types and with age. RE3 will explore the functional consequences SGR in primary neuronal and induced pluripotent stem cell (iPSC) models towards understanding the functional implications of disease enhanced SGR, and the therapeutic opportunities that SGR unveils.

IC Name
NATIONAL INSTITUTE ON AGING
  • Activity
    R56
  • Administering IC
    AG
  • Application Type
    1
  • Direct Cost Amount
    895820
  • Indirect Cost Amount
    499529
  • Total Cost
    1395349
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    866
  • Ed Inst. Type
  • Funding ICs
    NIA:1395349\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    ZRG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
  • Organization Department
  • Organization DUNS
    020520466
  • Organization City
    LA JOLLA
  • Organization State
    CA
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    920371005
  • Organization District
    UNITED STATES