# Vulnerability of Aging White Matter to Ischemia

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $310,386

## Abstract

Abstract
Stroke is a leading cause of death and disability and the risk for stroke increases with age. The mechanisms
that contribute to post-ischemic injury after stroke are not completely understood, and as a result most clinical
trials conducted to date for stroke therapeutics have failed. Failure to consider white matter (WM) injury is a
critical gap in the development of successful stroke therapy. As mechanisms of WM injury differ from those in
gray matter and change with age, an ideal stroke therapeutic must not only be directed towards neuronal and
axonal protection across age, but also must restore function when applied after injury. One of our significant
research achievements during the previous funding cycle established that Class I HDAC activation contributes
to excitotoxicity during ischemia and contributes to oxidative injury during the post-ischemic period by impairing
mitochondrial structure and function. Class I HDAC inhibition promotes axon function recovery when applied
before or after ischemia in young and aging WM through unknown mechanisms. Our current proposal focuses
on the mechanisms of post-ischemic protection conferred by Class I HDAC inhibition in young and aging WM.
 While little is known about the gene regulatory mechanisms underlying this protective phenomenon, an
intriguing reciprocal relationship has emerged between levels of HDACs and miRNAs affecting cellular survival
following stroke. Among ischemia-regulated miRNAs, miR-331 is predicted to target Class I HDACs. Ischemia
up-regulates Class I HDAC levels in young and aging WM. Our preliminary findings show that ischemia led to
decreased levels of miR-331 concomitant with increased HDAC expression and HDAC inhibition upregulated
miR-331 above control levels. Consequently, an miR-331 mimic suppresses HDAC levels, indicating a
reciprocal regulation between Class I HDACs and miR-331. Furthermore, WM ischemia activates nitric oxide
synthase (NOS), leading to oxidative injury via mitochondrial dysfunction, and Class I HDAC inhibition
attenuates NOS activity. In light of this information, we propose to further extend these studies by testing our
novel hypothesis that Class I HDAC activation mediates WM ischemic injury by contributing to increased
oxidative stress, impairing mitochondrial function, and down-regulating glial expression of miR-331.
Our overall goal is to determine whether Class I HDACs act directly or recruit NOS or interact with miR-331 to
exert post-ischemic injury in young and aging WM. Electrophysiological, biochemical, and mouse genetic in
vitro and in vivo approaches will be employed to test the following Specific Aims: Aim 1 is designed to
investigate whether Class I HDAC activation recruits NOS in an age-, cell-, and isoform-specific manner; Aim 2
is designed to determine whether Class I HDAC activation directly mediates mitochondrial injury during
ischemia; and Aim 3 is designed to establish whether Class I HDACs interact with miR-331 to mediate
...

## Key facts

- **NIH application ID:** 10172740
- **Project number:** 7R01AG033720-10
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Selva Baltan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $310,386
- **Award type:** 7
- **Project period:** 2010-09-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10172740

## Citation

> US National Institutes of Health, RePORTER application 10172740, Vulnerability of Aging White Matter to Ischemia (7R01AG033720-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10172740. Licensed CC0.

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