# Novel Cellular and Molecular Regulation of Collateral Remodeling in Ischemic Stroke

> **NIH NIH R01** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2021 · $346,018

## Abstract

ABSTRACT
Leptomeningeal collateral circulation and remodeling has recently emerged as a powerful therapeutic target for
neurorestorative therapy following stroke. Cerebral vascular occlusion prevents adequate blood flow to neural
tissue regions resulting in neuronal cell loss and severe sensorimotor deficits. Retrograde reperfusion occurring
in patients with a sufficient collateral response, either prior to or following recanalization, can help stabilize
cerebral blood flow (CBF) and aide in penumbral tissue protection. However, the cellular and molecular
mechanism(s) underlying this differential patient response in the collateral niche remains unclear. Evidence
suggests that endothelial cells (ECs) lining the collateral vessel wall actively respond to changes in blood flow
following obstruction and help orchestrate the collateral remodeling process. Our novel pre-clinical findings
demonstrate, cell-to-cell contact proteins called Eph receptor tyrosine kinases (EphR), and their membrane
bound ephrin ligand(s), are present on cerebral collateral ECs and play a central role in limiting their response
in the murine brain following stroke. The research objectives outlined in this application focus on the novel growth
suppressive mechanism(s) of EphR signaling on collateral remodeling and neural functional recovery. EC-
specific deletion of EphR results in significant neuroprotection and restoration of CBF which reflects a
monumental change in collateral growth and production of pro-arteriogenic factors. We hypothesize that
activation of EphR signaling mediates acute neural tissue damage and dysfunction by suppressing the EC
response during collateral remodeling after stroke. To test this, we will employ cell-specific inducible knockout
and bone marrow chimeric mice. We will also investigate the relevance and mechanism(s) of injury-induced
collateral remodeling in neural recovery using loss- and reverse-of-function mini-osmotic infusion approaches.
These studies will reveal a novel mechanism suppressing the collateral response to stroke and provide
therapeutic support for targeting this pathway for the treatment and management of ischemic stroke.

## Key facts

- **NIH application ID:** 10197241
- **Project number:** 5R01NS112541-03
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** Michelle Lee Theus
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $346,018
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197241

## Citation

> US National Institutes of Health, RePORTER application 10197241, Novel Cellular and Molecular Regulation of Collateral Remodeling in Ischemic Stroke (5R01NS112541-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10197241. Licensed CC0.

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