# Targeting blood-derived integrin signaling after stroke

> **NIH NIH R01** · EAST TENNESSEE STATE UNIVERSITY · 2020 · $323,750

## Abstract

Project Summary. We found that female, but not male, mice have increased plasma vitronectin (VTN) levels
and less tissue loss upon genetic VTN deletion after a stroke by temporary middle cerebral artery occlusion
(MCAO). This female-specific detrimental role of VTN may be relevant to women because that have worse
functional neurological outcomes after stroke. Therefore, this proposal focuses on female mice. We also find
that VTN leaks into the brain after MCAO and induces pro-inflammatory cytokine expression. Our in vitro and
in vivo data suggest that VTN acts through specific av integrins and possibly through uPAR. Integrins activate
intracellular signaling through focal adhesion kinase (FAK). Female mice injected systemically with an FAK
inhibitor 6 h after a stroke had better much better outcomes. These data suggest that VTN-Integrin-FAK
signaling contributes to tissue loss after stroke. Aim 1 will determine whether individual differences in
increased VTN levels in the blood seen after MCAO predict the inflammatory response and loss of brain tissue.
This might provide an additional prognostic stroke marker and open new opportunities to develop treatments.
We will also determine whether VTN and FAK inhibition act through astroglial or microglial FAK, two early
responder cell types with known significant contributions to inflammation. We will identify the most efficacious
post-MCAO time and duration of systemic treatments with the FAK inhibitor to improve outcomes, including
long-term locomotor function and also test this in aged “post-menopausal” female mice because stroke occurs
mainly in older people, with worse outcomes after menopause. FAK inhibitors are currently in clinical trials for
cancer and seem to be well tolerated. Aim 2 will define the extent to which the specific VTN receptors mediate
the VTN effects, using pharmacological and genetic approaches after MCAO in vivo. This aim will help to
identify molecular targets and treatments that may be more selective than FAK inhibition. Aim 3 will define
whether the higher IL-6 induction in the female brain after MCAO is neuroprotective, as has been reported for
males, and whether blood IL-6 levels, which are higher after stroke, contribute to induction of VTN. We will
also determine whether female sex hormones regulate VTN and whether VTN counteracts the protective
effects of estrogen and progesterone. Together, these studies focus on a novel and unique molecular target
that contributes to worse outcomes, and will provide new avenues for developing drug treatments after stroke,
perhaps specifically for women.

## Key facts

- **NIH application ID:** 9923009
- **Project number:** 5R01NS102745-03
- **Recipient organization:** EAST TENNESSEE STATE UNIVERSITY
- **Principal Investigator:** THEO HAGG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $323,750
- **Award type:** 5
- **Project period:** 2018-07-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923009

## Citation

> US National Institutes of Health, RePORTER application 9923009, Targeting blood-derived integrin signaling after stroke (5R01NS102745-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9923009. Licensed CC0.

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