Stroke results in immense health and economic burden. Current strategies to improve stroke outcome is fibrinolysis of the clot with tissue plasminogen activator and mechanical thrombectomy, which involves reperfusion of the ischemic region. However, accumulating evidence suggests that cerebral reperfusion is often accompanied by oxidative stress, thrombosis, and vascular inflammation, which exacerbates neuronal death in the ischemic penumbra. There is currently no effective intervention available to protect the brain damage following reperfusion therapy. Clinical studies have shown a positive correlation between the massive influx of neutrophils and severity of injury following reperfusion. Integrin alpha9beta1 is highly expressed on neutrophils (relative to monocytes), upregulated upon activation and transmigration, and is known to stabilize neutrophil adhesion to activated endothelium in synergy with alpha2beta1 integrin. The mechanistic role of alpha9beta1 in stroke outcome is not explored yet. Utilizing novel mutant strains, in pilot studies, we found that alpha9beta1 exacerbates stroke outcome by modulating thrombosis and vascular inflammation. Following updated Stroke Therapy Academic Industry Roundtable (STAIR) pre-clinical guidelines and compelling pilot data, we propose to test the innovative hypothesis that integrin alpha9beta1 contributes to ischemic stroke exacerbation in stroke models with comorbidities and therapeutic targeting alpha9beta1 will improve stroke outcome by limiting thrombosis and inflammation. To accomplish this, we will utilize complementary genetic and pharmacological approaches, state-of-the-art intravital microscopy, magnetic resonance imaging, laser speckle imaging and follow current STAIR/RIGOR guidelines. Aging and biological sex are key determinants that influence stroke outcome. We will determine whether targeting alpha9beta1 will improve stroke outcome in the context of biological sex and aging so that the observed effect is generalizable to the broader context. This project may have significant clinical implications since understanding the mechanisms by which neutrophils contribute to reperfusion injury in stroke models with comorbidities may provide new therapeutic interventions to treat ischemic stroke.

Public Health Relevance

Utilizing myeloid and neutrophil-specific alpha9beta1 deficient mice, the proposed studies will define the novel role of alpha9beta1 in the pathophysiology of ischemic stroke, serious health and economic problem in the United States. Furthermore, we will determine if targeting alpha9beta1 will improve stroke outcome in stroke models with comorbidities, and, thereby, could be developed as a therapeutic strategy towards better management of patients at high risk for stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS109910-02
Application #
9831089
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Bosetti, Francesca
Project Start
2018-12-01
Project End
2023-11-30
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242