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Investigating the cause of cerebral blood flow reductions in a mouse model of frontotemporal dementia

Award Number: R21AG075798
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Investigating the cause of cerebral blood flow reductions in a mouse model of frontotemporal dementia - Summary: Substantial reductions in brain blood flow are found in patients and mouse models of neurodegenerative diseases, including frontotemporal dementia (FTD). These blood flow reductions likely contribute to disease symptoms and progression, but the mechanism remains unknown. Recently, two new mechanisms contributing to brain blood flow reductions in Alzheimer's disease were proposed. Interestingly, both capillary stalling and pericyte constriction are associated with microvasculature dysfunction. In preliminary experiments, the PI has shown that capillary stalling found in Alzheimer's disease mice, also occurs in Progranulin (PGRN) deficient mice, a model for FTD. Thus, the project proposed here will investigate the contribution of stalled blood flow and pericyte constriction in capillaries to brain blood flow reductions. Further, this project aims to elucidate the mechanism behind these phenomena using transcriptome analyses and cell-surface proteomics of microvessels from PGRN-deficient mice. The pathology and region predicted to suffer from blood flow reductions in the PGRN deficient mice is the prefrontal cortex, which can be readily studied with the two-photon excited fluorescence imaging tools used previously by the PI. Preliminary data suggests that PRGN-deficient mice display increased capillary stalling caused by white blood cells adhered to the endothelium. For Aim 1, we will use high-resolution, multiphoton, in vivo imaging approaches to structurally and functionally determine blood flow rates in individual capillaries, measure capillary stalling and pericyte constriction, and their interplay. This data will identify the cause of brain blood flow reduction associated with FTD. Aim 2 will elucidate the molecular mechanism linking vascular inflammation to brain blood flow reductions in PGRN-deficient mice by using transcriptomic and cell-surface proteomics to profile microvessels. These experiments will generate two datasets that will allow us to pinpoint molecular aberrations in microvessels of PGRN deficient mice. The data will also shed light on the role of vascular inflammation and vascular obstructions contributing to blood flow reductions. Selected genes and proteins identified in these screens will be independently confirmed and later further analyzed by functional in vivo multiphoton imaging, labeling antibodies, inhibiting drugs, and/or cell-type-specific mouse models. We predict that candidate genes and proteins will be involved in vascular inflammation and associated with oxidative stress, blood-brain barrier breakdown, protein degradation, and lysosomal dysfunction. The idea of capillary stalling is new, and - if confirmed -, could represent a mechanism contributing to brain blood flow reductions in neurodegenerative disease in general, and not just specifically to FTD. If correct, novel therapeutic strategies targeting microvascular inflammation could be developed to improve brain blood flow in patients with FTD and possibly in other neurogenerative diseases with reductions in brain blood flow.


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 = -$2,844 )
2026	2022	UNIVERSITY OF MIAMI	1320 SOUTH DIXIE HIGHWAY STE 650	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Aging Research	000	1	1/8/2026	NEW	-$2,844
														Subtotal = -$2,844

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	UNIVERSITY OF MIAMI	1320 SOUTH DIXIE HIGHWAY STE 650	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Aging Research	000	1	11/25/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF MIAMI	1320 SOUTH DIXIE HIGHWAY STE 650	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Aging Research	000	1	6/17/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $22,942 )
2023	2023	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 650	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Aging Research	000	1	11/27/2022	SUPPLEMENT FOR EXPANSION	$22,942
														Subtotal = $22,942

Issue Date FY: 2022 ( Subtotal = $410,845 )
2022	2022	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 650	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Aging Research	000	1	7/25/2022	NEW	$410,845
														Subtotal = $410,845

Grand Total All Awards = $430,943

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Investigating the cause of cerebral blood flow reductions in a mouse model of frontotemporal dementia

Award Number: R21AG075798

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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