# Novel Targets and Therapeutic Interventions against Cerebral Ischemia-Reperfusion Injury

> **NIH NIH R01** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2021 · $597,643

## Abstract

Project Summary/Abstract
The cerebral ischemia/reperfusion (I/R) injury is a major challenge for the treatment of patients with acute
ischemic stroke by intravenous (IV) thrombolysis and endovascular therapy. Currently, there is no effective
intervention available to treat/prevent cerebral I/R injury. Emerging evidence suggests that thrombotic and
inflammatory responses (thrombo-inflammation) and aberrant endoplasmic reticulum (ER) stress in the brain
elicited by cerebral I/R contributes importantly to secondary brain injury and neurologic deterioration. In this
proposal we wish to develop a novel miRNA-based therapeutic strategy to simultaneously target these
pathological processes of cerebral I/R injury through distinct molecular mechanisms. Recently, decreased
expression of miR-30c has been implicated in many pathological conditions in both patients and animal models.
In preliminary studies, we show that miR-30c is highly expressed in blood platelets, cerebral microvessels, and
cortical/hippocampal neurons in normal mice but its levels decline with age. miR-30c levels in both blood and
brain are markedly decreased after ischemic stroke and elevating miR-30c by single IV injection of synthetic
miR-30c mimic significantly protects against cerebral I/R injury. We further show that the increased expressions
of the direct target genes of miR-30c (including PAI-1 in both blood and brain, elF2α and caspase-3 in the brain)
induced by cerebral I/R injury were significantly decreased by IV miR-30c mimic treatment. Based on these
exciting new findings from young adult mice, we propose the innovative hypothesis that miR-30c functions as a
critical regulator of thrombo-inflammation and ER stress in the ischemic brain elicited by cerebral I/R injury, and
thus targeting miR-30c represents a novel therapeutic approach for combating cerebral I/R injury. Following
updated stroke Therapy Academic Industry Roundtable (STAIR) pre-clinical guidelines, we will test this
hypothesis in aged male and female mice. Specifically, we will determine the efficacy and safety of IV miR-30c
mimic as novel stroke therapeutics (Aim1). Using complementary approaches, i.e. the “gain-of-function” (miR-
30c mimic) and “loss-of-function” (anti-sense Morpholino oligos that are designed to specifically compete with
miR-30c for binding sites of 3’UTR of each individual target gene and thus acts as a “target protector”), we will
identify PAI-1 as a key molecular target of miR-30c in regulation of post-stroke thrombo-inflammation (Aim 2),
and identify elF2α and caspase 3 as key molecular targets of miR-30c in regulation of post-stroke neuronal ER
stress and neuronal cell death (Aim 3). The long-term goal of these studies is to evaluate if targeting miR-30c is
a viable option for stroke therapy in both male and female older populations at high risk for stroke.

## Key facts

- **NIH application ID:** 10297340
- **Project number:** 1R01NS119538-01A1
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** Guohong Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $597,643
- **Award type:** 1
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10297340

## Citation

> US National Institutes of Health, RePORTER application 10297340, Novel Targets and Therapeutic Interventions against Cerebral Ischemia-Reperfusion Injury (1R01NS119538-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10297340. Licensed CC0.

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