# Novel Targets for Stroke Intervention - Gene Discovery for Modulators of Infarction

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $638,289

## Abstract

Occlusion of the blood vessels supplying the brain leads to ischemic stroke and
infarction—irreversible death of brain tissue. Risk factors causing stroke, especially those involving lipid
metabolism, form the basis of current therapies to reduce stroke risk. However, despite decades of
research on the molecular events occurring during infarction, the translation of these discoveries to
“druggable” targets to treat stroke outcome (death of brain tissue) has been quite disappointing. Novel
approaches will be required to identify new and more physiologically relevant targets. The scientific
premise of our proposal is that naturally occurring allelic variation underlies the profound differences in
seen in stroke outcomes and that these neuro-protective gene variants would provide a novel path
towards new targets for stroke treatment. However, genetic mapping approaches for infarct size in the
human (e.g., GWAS of infarct volume among ischemic stroke patients) are intrinsically problematic due
to wide variation in the extent and location of the occluded vessel, and especially, variation in the time
window between first recognized symptoms and medical intervention. To date, we can find no published
GWAS for infarct volume in ischemic stroke. The Marchuk lab has taken an alternative, forward genetic
approach to discover novel genes modulating infarction. We have surgically occluded the distal middle
cerebral artery in over 35 inbred mouse strains and found that infarct volume differs more than 50-fold.
These robust and highly reproducible differences in infarct size are at least 10-fold larger than that seen
in any engineered mouse lines but, importantly, are caused by natural allelic variation in the mouse
genome. We have mapped several of these genetic loci and the goals of Aims 1 and 2 are to identify
these novel genes regulating in infarct size. However, this gene discovery approach has required in vivo
surgical assays in thousands of adult animals. We need a more scalable yet physiologically relevant
screening platform to transform this approach to full genome-wide scale. The Lo lab has pioneered the
development of such a discovery platform for cerebral infarction, simulating stroke by Oxygen/Glucose
Deprivation (OGD; a well-characterized model for ischemic injury) in ex vivo brain tissue explants. Unlike
isolated neurons in culture, brain slice explants retain the complex multicellular nature of the intact organ,
and thus retain and represent the complex intercellular interactions occurring in brain tissue during
cerebral infarction. In Aims 1 and 2, this ex vivo OGD platform will be used to identify the causative
genes in our previously mapped loci. Our experience gained in these aims will lead to Aim 3, where the
ex vivo OGD assay will be used to directly map and identify novel cerebral infarction genes, using the
genetic mapping resource population of the Collaborative Cross. Our study takes advantage of
innovative approaches developed by the ...

## Key facts

- **NIH application ID:** 9830698
- **Project number:** 5R01NS100866-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Scott R Floyd
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $638,289
- **Award type:** 5
- **Project period:** 2017-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830698

## Citation

> US National Institutes of Health, RePORTER application 9830698, Novel Targets for Stroke Intervention - Gene Discovery for Modulators of Infarction (5R01NS100866-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9830698. Licensed CC0.

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