# Cerebral Arteriole Structure/Function in Diabetic Ischemic Brain Injury

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2024 · —

## Abstract

Over half of the 5.8 million Americans who suffer from dementia have Vascular contributions to Cognitive
Impairment and Dementia (VCID), for which there are NO effective treatments. The focus on neuronal
pathologies of the disease limited our understanding of the cellular/molecular mechanisms that promote the
onset and progression of cognitive decline at the neural-glial-vascular (NGV) interface and stalled the
development of any effective therapeutic strategies. While it is known that diabetes increases the risk and
severity of VCID, the inadequate integration of diabetes experimental VCID research has widened this vast
knowledge gap. The specific objective of this renewal proposal is to address these gaps by defining cellular
mechanisms contributing to the progressive disruption of the NGV unit using diabetes and stroke as disease
models. While neurological diseases have long been categorized as vascular, neurodegenerative or
inflammatory, it is now recognized that these mechanisms are interwoven. Our exciting findings in the past
funding period led us to focus on the mechanisms of complex interaction within the NGVU: 1) diabetic male and
female rats display cognitive deficits that are worsened after stroke and accompanied by exhibit extensive
remodeling at the NGV interface, 2) cells that survive initial injury lose their neurotrophic/proangiogenic
properties and become inflamed in both sexes, 3) mature brain derived neurotrophic factor (mBDNF) is
decreased while proapoptotic proBDNF & its cognate receptor p75NTR are increased in the diabetic brain and
brain microvascular endothelial cells (BMVECs), 4) unlike control rats that show a dynamic switch between
anti/pro-inflammatory microglia after stroke, diabetic rats display sustained proinflammatory microglia and
microglia knockdown in the early poststroke period improves sensorimotor and cognitive outcomes, 5)
endothelial expression of senescent markers is amplified in diabetic rats after ischemic injury, 6) interleukin-1
(IL-1), its receptor and phosphorylated tau (p~tau) are increased in BMVECs under inflammatory stress, and
7) cilostazol, a clinically approved vasodilator with senostatic/anti-inflammatory properties that is on current
clinical trials for the prevention of progressive cognitive impairment in stroke survivors, improves endothelial
inflammation as well as cognition in diabetic rats. Two aims with translational and mechanistic studies will test
the central hypothesis is that diabetes-mediated premature endothelial senescence promotes vasotrophic
uncoupling and endothelial tau pathology, collectively propagating senescence-associated inflammation within
the NGVU after brain injury leading to progressive VCID. Aim 1 will determine the causal role of endothelial
(e)senescence in progressive VCID in diabetes by defining a) a) the impact of cell specific inhibition of
senescence via endothelial (e)p16 knockdown or intranasal delivery of cilostazol in VCAM1-tagged
nanoparticles on t...

## Key facts

- **NIH application ID:** 10768623
- **Project number:** 5I01BX000347-16
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** ADVIYE ERGUL
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-10-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10768623

## Citation

> US National Institutes of Health, RePORTER application 10768623, Cerebral Arteriole Structure/Function in Diabetic Ischemic Brain Injury (5I01BX000347-16). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10768623. Licensed CC0.

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