The role of senescence and endothelial to mesenchymal transition in the aging cerebral vasculature

Active Project Grant Awarded Last action

Award ID
F31AG099660
Recipient
Awarding agency
Obligated
$77,200

Award facts

Assistance listing
93.866 Aging Research
Completion date 0% complete
Originally
Place of performance
Oklahoma City, OK 73104, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

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.

Transactions

Action Obligated Date
Amendment $0
Amendment $38,600
Amendment $38,600
Original award $0

Quick answers

Who received award F31AG099660?

F31AG099660 was awarded to University Of Oklahoma by National Institute on Aging (National Institutes of Health) on November 26, 2026.

How much is award F31AG099660 worth?

$77,200 has been obligated on F31AG099660.

On GovTribe

See this award's full record

  • Every transaction and subaward
  • The recipient's other awards and teaming partners
  • Similar grant awards
  • Ask GovTribe AI about this award
Try for free Login