Tuesday, July 1, 2025 7/1/2025

Strategies for targeting astrocyte reactivity in Alzheimer's disease and related dementias

Award Number: P01AG078116
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Strategies for targeting astrocyte reactivity in Alzheimer's disease and related dementias - OVERALL – ABSTRACT SUMMARY This P01— Strategies for Targeting Astrocyte Reactivity in AD and ADRD (STAR-ADRD) addresses the (patho)physiologic roles of reactive astrocytes in Alzheimer’s disease (AD) and related dementias (ADRD). Though highly significant to many disease phenotypes, astrocyte functions are under-investigated and have yet to benefit from large-scale programmatic support from the NIH. To fill this void we have assembled a highly accomplished and collaborative team from the University of Kentucky Sanders-Brown Center on Aging (UK- SBCoA). The overarching goals of this project are to: (1) Use cell-specific targeting to modulate distinct aspects of the reactive astrocyte phenotype. (2) Use cutting-edge technologies to assess the functional impact of reactive astrocytes in intact preclinical mouse models of AD and ADRD pathologies. (3) Leverage UK-SBCoA and UK- Alzheimer’s Disease Research Center (ADRC) resources to validate preclinical results in postmortem and living human subjects. And (4) Use an integrated data pipeline approach to analyze and interpret data within and across projects. Through these aims we will test the hypothesis that: interrelated reactive astrocyte phenotypes drive major pathophysiologic features of dementia including cerebrovascular dysfunction, hypometabolism, and impaired neuronal network function and fidelity. Projects are designed around a clear understanding that dementia does not exist as a single pathological entity most of the time, but rather is characterized by multiple brain pathologies. Project 1 (Astrocytic end-feet and VCID) will use MMP9 overexpression/knockdown in a model of cerebral small vessel disease to address astrocyte endfeet degeneration. Project 2 (Astrocytic insulin signaling and AD) will overexpress/knockdown astrocytic insulin receptors (IR) in an Aβ model to study the impact of impaired astrocytic IR signaling. Project 3 (Astrocytic glutamate transport in AD and VCID) will overexpress/knockdown the astrocytic glutamate transporter SLC1A2 in a mixed Aβ-vascular model to assess the role of impaired glutamate transport in reactive astrocytes. Project 4 (Astrocytic KATP channels in LATE+HS) will overexpress/eliminate astrocytic ABCC9/SUR2 in a model of LATE + hippocampal sclerosis to assess the role of KATP channels. Four Cores will support and further integrate our Projects. Core B: Animal Vascular-Metabolic-Neural Network (VMN) will assess cerebrovascular, metabolic, and neural network properties in mice using two-photon microscopy, MRI/MRS, microelectrode array neuro- chemistry, and electrophysiology. Core C: Human Consultation-Biosamples-Biomarkers (CBB) will validate results in mice using well characterized autopsy tissue, MRI, EEG, and fluid biomarker data from humans. And Core D: Data Management and Biostatistics will establish a data pipeline for efficient categorization, transformation, and statistical analysis of complex relationships between astrocyte interventions and endpoint measures, within and between projects. Finally, an Administrative Core (Core A) will provide leadership, coordination, integration, and administrative structure, so that the P01 goals are achieved.


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 = $4,188,139 )
2025	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	001	4	5/27/2025	NON-COMPETING CONTINUATION	$3,958,139
2025	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	3	3/14/2025	SUPPLEMENT FOR EXPANSION	$230,000
														Subtotal = $4,188,139

Issue Date FY: 2024 ( Subtotal = $4,131,531 )
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	3	6/26/2024	NON-COMPETING CONTINUATION	$4,131,531
														Subtotal = $4,131,531

Issue Date FY: 2023 ( Subtotal = $4,531,286 )
2023	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	2	8/1/2023	NON-COMPETING CONTINUATION	$4,150,513
2023	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	001	2	8/16/2023	SUPPLEMENT FOR EXPANSION	$380,773
														Subtotal = $4,531,286

Issue Date FY: 2022 ( Subtotal = $4,222,772 )
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	1	8/31/2022	NEW	$4,222,772
														Subtotal = $4,222,772

Grand Total All Awards = $17,073,728

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Strategies for targeting astrocyte reactivity in Alzheimer's disease and related dementias

Award Number: P01AG078116

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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