Thursday, January 1, 2026 1/1/2026

Cell-type-specific functions of GPR3 in Alzheimer’s disease

Award Number: R01AG058851
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Cell-type-specific functions of GPR3 in Alzheimer’s disease - PROJECT SUMMARY Alzheimer’s disease (AD) is a major unresolved public health issue. Despite decades of research on amyloid-β (Aβ) and tau, we do not fully understand the complex molecular and cellular biology of these key disease drivers. The brain reacts to the pathological accumulation of Aβ and tau with an early and profound neuroinflammatory response, which includes alterations in the profile, function, and activation of microglia, astrocytes, and oligodendrocytes. Although neuroinflammation is an integral component and putative driver of AD pathogenesis, the cell type-specific mechanisms that characterize this response and its impact on cognitive decline are incompletely understood. Biased G protein-coupled receptor (GPCR) ligands preferentially activate G protein or β-arrestin signaling pathways and are leading to the development of drugs with superior efficacy and reduced side effects in several therapeutic areas. Surprisingly, biased GPCR signaling is a largely unexplored area in AD research. In the previous funding cycle, we developed a G protein-biased GPCR 3 (GPR3) mouse model that lacks GPR3- mediated β-arrestin signaling. Using this model, we showed that biased GPR3 mice exhibit normal cognitive and behavioral functions, which are disrupted in Gpr3-deficient mice. We further determined that biased GPR3 signaling reduces Aβ levels and the Aβ plaque burden and enhances the glial response in a preclinical AD mouse model. These exciting findings indicate that GPR3 is the first GPCR to modulate both Aβ pathology and the innate immune response in AD. These studies also establish the strong scientific premise that the largely unknown cell type-specific functions of GPR3 impact the development and progression of AD. Thus, the major goal of this R01 renewal application is to test the central hypothesis that biased GPR3 signaling in microglia, astrocytes, and neurons reduces AD-related pathologies and cognitive decline by promoting protective immune responses and preserving neuronal function. Aim 1 will determine how biased GPR3 signaling alters microglia activation and function and AD-related pathways in primary human microglia and in vivo in our AD mouse models. Aim 2 will determine how biased GPR3 signaling affects the cell-autonomous and non-cell-autonomous functions of astrocytes in primary human astrocytes and in vivo in our AD mouse models. Aim 3 will determine the role of biased GPR3 signaling in neuronal function and cognition in directly converted induced neurons (iNs) from control subjects and AD patients and in vivo in our AD mouse models, respectively. Successful completion of these studies will establish the in vitro and in vivo impact of biased GPR3 signaling on neuronal- and glial- dependent pathways and provide proof of concept for the development of safer and more selective GPCR- targeting therapeutics with more directed pharmacological action for AD.


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: 2026 ( Subtotal = $634,806 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	000	8	11/26/2025	NON-COMPETING CONTINUATION	$634,806
														Subtotal = $634,806

Issue Date FY: 2025 ( Subtotal = $724,903 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	002	7	12/9/2024	NON-COMPETING CONTINUATION	$665,726
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	004	7	8/4/2025	NON-COMPETING CONTINUATION	$59,177
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	003	7	1/15/2025	NON-COMPETING CONTINUATION	$0
2025	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	001	6	11/20/2024	COMPETING CONTINUATION	$35
2025	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	000	5	11/20/2024	NON-COMPETING CONTINUATION	-$35
														Subtotal = $724,903

Issue Date FY: 2024 ( Subtotal = $607,300 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	001	6	11/9/2023	COMPETING CONTINUATION	$607,300
2024	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	000	5	11/1/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $607,300

Issue Date FY: 2022 ( Subtotal = $386,478 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	000	5	1/11/2022	NON-COMPETING CONTINUATION	$347,830
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Aging Research	001	5	6/7/2022	NON-COMPETING CONTINUATION	$38,648
														Subtotal = $386,478

Issue Date FY: 2021 ( Subtotal = $386,617 )
2021	2021	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	000	4	2/3/2021	NON-COMPETING CONTINUATION	$386,617
														Subtotal = $386,617

Issue Date FY: 2020 ( Subtotal = $386,752 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	000	3	1/17/2020	NON-COMPETING CONTINUATION	$386,752
														Subtotal = $386,752

Issue Date FY: 2019 ( Subtotal = $386,883 )
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	000	2	1/17/2019	NON-COMPETING CONTINUATION	$386,883
														Subtotal = $386,883

Issue Date FY: 2018 ( Subtotal = $386,404 )
2018	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Aging Research	000	1	3/22/2018	NEW	$386,404
														Subtotal = $386,404

Grand Total All Awards = $3,900,143

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Cell-type-specific functions of GPR3 in Alzheimer’s disease

Award Number: R01AG058851

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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