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Brain pericyte contractility, cerebral blood flow and blood-brain barrier integrity are impaired by normal aging and Alzheimer's disease amyloid-beta and are dependent on p75NTR

Award Number: R00AG058780
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ ABSTRACT Neurovascular dysfunction has been linked to Alzheimer’s disease (AD) evolution in experimental, imaging, pathological, and epidemiological studies. These key findings have led to an emerging ‘neurovascular hypothesis’ of AD, which holds that cerebrovascular dysfunction contributes to the onset and progression of cognitive decline. There is growing appreciation and strong evidence that neurovascular uncoupling, cerebral blood flow (CBF) reductions and dysregulation, and breakdown of the blood-brain barrier (BBB), including the loss of pericytes, are early events in the AD pathophysiological cascade. Pericytes are mural cells on capillaries that are critical for the maintenance of the BBB, and have recently been implicated in the regulation of CBF. Importantly, pericytes deteriorate and the BBB degrades in AD. Based on our preliminary findings we hypothesize that pericytes are contractile cells that regulate capillary diameter and thereby CBF, and BBB integrity, and that this pericyte regulation is impaired in normal aging and in the presence of Aß40 and Aß42 via p75NTR pathway. To test this hypothesis, I will use cutting-edge approaches including in vivo two- photon/confocal brain vascular imaging to assess pericyte contractility, capillary diameter, CBF changes and BBB integrity. Brain tissue analysis will also be performed. I will determine if brain pericytes retain contractility, properly regulate CBF, and maintain BBB integrity in normal aging and in the presence of Aß40 and Aß42 (AIM 1/ K99). Also, I will determine if normal aging and Aß40 and Aß42 impair brain BBB integrity via p75NTR (AIM 2/ R00). Understanding how pericytes regulate CBF and BBB integrity in normal aging and AD and the involvement and potential of p75NTR as a therapeutic target for AD is timely and important. This K99/R00 grant is essential for my success in becoming an impactful tenure-track assistant professor because it provides me training in an essential technique to investigate neurovascular dynamics for future studies, and also will provide professional training in improving oral presentation and grant writing skills.


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: 2022 ( Subtotal = $218,200 )
2022	2022	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Aging Research	000	5	6/14/2022	NON-COMPETING CONTINUATION	$218,200
														Subtotal = $218,200

Issue Date FY: 2021 ( Subtotal = $251,633 )
2021	2021	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Aging Research	001	4	7/30/2021	NON-COMPETING CONTINUATION	$249,000
2021	2020	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Aging Research	000	3	2/3/2021	EXTENSION WITH OR WITHOUT FUNDS	$2,633
														Subtotal = $251,633

Issue Date FY: 2020 ( Subtotal = $249,000 )
2020	2020	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERISTY BLVD 380 ADMINISTRATION BLDG	MOBILE	AL	36688	MOBILE	USA	Aging Research	000	3	8/11/2020	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $249,000

Grand Total All Awards = $718,833

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Brain pericyte contractility, cerebral blood flow and blood-brain barrier integrity are impaired by normal aging and Alzheimer's disease amyloid-beta and are dependent on p75NTR

Award Number: R00AG058780

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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