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Sex chromosomal regulation of hippocampal microglial activation with Alzheimer's disease and aging

Award Number: DP5OD033443
ORGANIZATION: OFFICE OF THE DIRECTOR, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/13/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Sex chromosomal regulation of hippocampal microglial activation with Alzheimer's disease and aging - ABSTRACT Sex and age are the primary risk factors for Alzheimer’s disease (AD), the most common form of dementia. After decades of failed clinical trials for the treatment of Alzheimer’s disease (AD), there is an urgent need for creative approaches to uncover new therapeutic targets. While women experience a greater prevalence, more severe neuropathology, and greater cognitive decline with AD, men diagnosed with AD progress more quickly to death. However, little is known about the mechanisms (whether hormonal or sex chromosomal) driving the sex-biased response to AD pathology with brain aging. Our long-term goal is to identify the underlying mechanisms governing the sex-biased response to AD. Recent GWAS studies have identified several AD risk loci in genes exclusively expressed by microglia, shifting the field to explore potential causative roles of microglia in AD. As well, microglia show profound phenotypic sex differences with aging and AD. We hypothesize that sex differences in microglial responsivity contribute mechanistically to the sex-biased disease progression seen in AD. Although the onset of AD correlates to the menopausal transition in women, hormone replacement therapies (HRT) have generated mixed results. The formerly under-appreciated role of sex chromosomal contributions has recently come to the forefront in AD research, with a special emphasis on X-encoded histone modifiers. The objective of this study is to determine if sex chromosome complement (XX v. XY), independent of sex hormones, alters pathological progression and microglial activational profiles in AD and test the hypothesis that X-encoded lysine-specific demethylase Kdm6a contributes to the sexually divergent microglial response to AD. Our specific aims will test the following hypotheses: (Aim 1) sex chromosome complement alters survival and pathological progression (plaques/tangles, microgliosis) of AD; (Aim 2) sex chromosomally regulated differences in heterogeneous microglial cell responses to aging and AD are driven, in part, by alterations in histone modifications (H3K27me3); (Aim 3) microglial X-encoded Kdm6a expression is sufficient to cause sexually- divergent microglial response to AD through genome-wide, targeted removal of repressive H3K27me3. The paired phenotypic and multi-omic data generated in these studies will facilitate the identification of sex- differentially regulated genomic programs that confer protection or risk to the progression of AD in both sexes in order to prioritize targets for small molecule or epigenome editing for therapeutic intervention in AD. The research plan is innovative because we investigate sex differences in AD through the lens of sex chromosomes and utilize ground-breaking transcriptomic, epigenomic, and analytical techniques to gain a previously unattainable resolution of microglia heterogeneity.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Trans-NIH Research Support	000	3	6/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $437,000 )
2024	2024	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Trans-NIH Research Support	000	3	8/29/2024	NON-COMPETING CONTINUATION	$437,000
														Subtotal = $437,000

Issue Date FY: 2023 ( Subtotal = $437,000 )
2023	2023	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Trans-NIH Research Support	000	2	9/1/2023	NON-COMPETING CONTINUATION	$437,000
														Subtotal = $437,000

Issue Date FY: 2022 ( Subtotal = $437,000 )
2022	2022	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Trans-NIH Research Support	000	1	9/13/2022	NEW	$437,000
														Subtotal = $437,000

Grand Total All Awards = $1,311,000

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Sex chromosomal regulation of hippocampal microglial activation with Alzheimer's disease and aging

Award Number: DP5OD033443

ORGANIZATION: OFFICE OF THE DIRECTOR, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/13/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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