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Single-cell Epigenome Analysis of the Alzheimer's Disease Brain

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R43AG079691-01
Agency Tracking Number: R43AG079691
Amount: $499,475.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: NIA
Solicitation Number: PAS19-316
Solicitation Year: 2019
Award Year: 2022
Award Start Date (Proposal Award Date): 2022-09-30
Award End Date (Contract End Date): 2023-08-31
Small Business Information
Del Mar, CA 92014-3521
United States
DUNS: 117647710
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (858) 260-1119
Business Contact
Phone: (858) 344-1618
Research Institution

Title: Single-cell Epigenome Analysis of the Alzheimer’s Disease Brain (PI: Hartl)Alzheimer’s disease (AD) affects more than 6 million American but no cures and few effective treatments
are available. Genome-wide association studies (GWAS) have uncovered thousands of segregating mutations
that significantly increase AD risk. Most of these variants alter non-protein-coding sequence and lack clear
functional annotation, hindering efforts to translate risk-conferring mutations into curative or preventative
therapies. Heritability partitioning suggests that these variants likely perturb gene expression in glial cells
(especially microglia), ultimately leading to AD pathology. Linking these variants – and their downstream effects
– to specific regulatory networks and pathways has been hindered by a lack of cis-regulatory element maps for
these major glial cell classes and their subtypes. The proposed study addresses this critical knowledge gap by
applying a cutting-edge single cell multi-omic technology to postmortem human brain samples from
phenotypically normal donors and AD patients. Specifically, the chromatin accessibility or histone modifications
will be interrogated jointly with gene expression at single cell resolution in dorsolateral prefrontal cortex (DLPFC)
from multiple donors, to identify and characterize the cell-type-specific gene regulatory elements that drive
aberrant cell states and disease-relevant cellular responses in human AD brains. The single cell chromatin state
and gene expression atlases from phenotypically normal individuals will be compared to those from AD subjects
to determine the brain cell types, genes and regulatory elements that exhibit significant changes in pathological
conditions. Finally, the newly generated cell-type resolved epigenome maps will be integrated with public
genomic resources to provide functional annotation of the AD risk variants, identify disease-relevant cell types,
prioritize genes, transcription factors, and molecular pathways for future mechanistic investigation. Results of
the proposed study will provide a much-needed tool for study of AD pathogenesis and development of improved
AD therapies.

* Information listed above is at the time of submission. *

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