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The Role of Senescence and Endothelial to Mesenchymal Transition in the Aging Cerebral Vasculature

Award Number: F31AG099660
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/20/2026
PERIOD OF PERFORMANCE END DATE: 07/19/2029

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The Role of Senescence and Endothelial to Mesenchymal Transition in the Aging Cerebral Vasculature - PROJECT SUMMARY/ABSTRACT Recent advancements in medicine have resulted in an increase in lifespan in aged populations; however, this increase in lifespan is not always matched with an increase in health span. Vascular cognitive impairment and dementia (VCID) is the second leading cause of cognitive impairment in the aged population. VCID is defined as any cognitive decline resulting from underlying vascular pathologies (including vascular fragility leading to cerebral microhemorrhage formation, impaired neurovascular coupling, and blood-brain barrier disruption). Vascular fragility, and subsequent vascular dysfunction, leads to improper perfusion of the highly metabolic brain. This improper perfusion results in cognitive decline and downstream gait irregularities decreasing quality of life in elderly populations. It is well understood that senescent cells (cells that have undergone cell cycle arrest) increase with age. These cells acquire a senescence-associated secretory phenotype rich in pro-inflammatory cytokines and chemokines. The presence of senescent cells, and their senescence-associated secretory phenotype, exacerbate the cerebrovascular pathologies associated with VCID; however, the cellular mechanisms underlying how senescent cells promote age-related vascular fragility are not well understood. One potential mechanism by which senescent cells may promote vascular fragility is via endothelial to mesenchymal transition (EndMT). During EndMT, endothelial cells lose their characteristic endothelial phenotype important for cerebrovascular function (marked by a loss of endothelial cell-specific markers, decreased cell-cell adhesion, and decreased barrier formation) and gain a mesenchymal-like phenotype. Of interest, many of the stimuli that are known to trigger EndMT are found in the senescence-associated secretory phenotype (i.e. proinflammatory cytokines and chemokines). The goal of this proposal is to determine if age-related increases in senescent cells, and their senescence-associated secretory phenotype, drive EndMT in neighboring endothelial cells of the aging brain leading to cerebrovascular fragility and downstream gait deficits. Aim 1 of this proposal will investigate if cellular senescence contributes to EndMT in the aging brain by using in vitro assays and endothelial cell lineage tracing mice coupled with single-cell ATAC-seq. Aim 2 of this proposal will investigate if blocking EndMT, through removal of a transcriptional regulator important for EndMT (Heyl), results in reduced age-related vascular fragility. In vitro assays and analysis of hypertension-induced cerebral microhemorrhage formation/gait deficits in mice with endothelial cell-specific knockout of Heyl will be used to answer this question. The completion of this work will reveal cellular mechanisms underlying age-associated vascular fragility in the brain potentially leading to new therapeutic targets to combat vascular dementia and increase health span.


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 = $38,600 )
2026	2026	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 560	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	001	1	5/27/2026	NEW	$0
2026	2026	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 560	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	1	5/27/2026	NEW	$38,600
2026	2026	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 560	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	002	1	7/29/2026	NEW	$0
														Subtotal = $38,600

Grand Total All Awards = $38,600

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The Role of Senescence and Endothelial to Mesenchymal Transition in the Aging Cerebral Vasculature

Award Number: F31AG099660

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/20/2026

PERIOD OF PERFORMANCE END DATE: 07/19/2029

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