# NO SYNTHASE GENE EXPRESSION AND CEREBRAL ISCHEMIC DAMAGE

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $370,781

## Abstract

Cerebral ischemia triggers a powerful innate immunity response initiated by danger associated
molecular pattern molecules (DAMPs) released by damaged cells. Engagement of innate
immunity receptors on resident brain cells, mainly microglia, triggers production of cytokines and
adhesion molecules leading to an inflammatory response that contributes to the acute phase of
the injury. Post-ischemic inflammation is considered an attractive therapeutic target, but a
deeper understanding of the upstream molecular events is needed to inform therapeutic
development. Studies over the previous funding period have demonstrated that the innate
immunity receptor CD36 promotes the activation and neurotoxicity of neutrophils, a key effector
of the acute damage produced by post-ischemic inflammation, and contributes to ischemic
injury. These harmful effects are attributable to CD36 expression in microglia and endothelial
cells, not in infiltrating hematogenous cells, but the relative roles that microglial and endothelial
CD36 play in post-ischemic inflammation have not been established. IL1, secreted by
microglia, has emerged as a key cytokine involved in the initiation of post-ischemic
inflammation. IL1 is produced by the inflammasome, a multimolecular complex that when
activated by DAMPs leads to the cleavage of pro-IL1 into the mature cytokine. We hypothesize
that CD36 in microglia mediates IL1 production by participating in inflammasome activation.
IL1, in turn, acts on endothelial cells to produce, in concert with CD36, potent neutrophil
activators, including CSF3, and triggering neutrophil cytotoxicity. This hypothesis will be tested
using a well-established mouse model of transient focal ischemia. In vivo and in vitro
approaches, as well as CD36 “floxed” mice enabling targeted deletion of CD36 in specific cell
types will be used. Since stroke is a disease of the aged in both sexes and aging enhances the
deleterious effects of microglia and CD36, we will also study aged male and female mice. Aim 1
will test the hypothesis that CD36 contributes to post-ischemic IL1 production by microglia
through the NLRP3 inflammasome. Aim 2 will test whether microglial IL1 acts on endothelial
IL1 receptors to induce CSF3 production and neutrophil activation in concert with endothelial
CD36. Aim 3 will use mice with microglial or endothelial CD36 deletion to assess the impact of
the molecular pathways defined in Aims 1 and 2 on the histological and functional outcomes of
cerebral ischemia. These studies may unveil a novel microglia-endothelial axis whereby
microglial CD36 acts as an upstream “sensor” regulating IL1 secretion and endothelial CSF3
production through CD36, ultimately leading to neutrophil activation and tissue damage.

## Key facts

- **NIH application ID:** 10131271
- **Project number:** 5R01NS034179-26
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Costantino Iadecola
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $370,781
- **Award type:** 5
- **Project period:** 1995-03-20 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10131271

## Citation

> US National Institutes of Health, RePORTER application 10131271, NO SYNTHASE GENE EXPRESSION AND CEREBRAL ISCHEMIC DAMAGE (5R01NS034179-26). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10131271. Licensed CC0.

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