Transcriptomics of Stroke Thrombus to Determine Stroke Etiology and Response to Revascularization Therapies - PROJECT SUMMARY/ABSTRACT This is a K23 award application for Dr. James Giles, a neurologist and young investigator pursuing patient- oriented clinical research on ischemic stroke caused by large vessel occlusion. A K23 award will provide him with the means to acquire critical skills in four key development areas: 1) computational biology for transcriptomic analysis of tissue and blood samples, 2) the biology of thrombosis in patients with acute ischemic stroke, 3) clinical translational project management and 4) research management and leadership. By acquiring these skills, Dr. Giles will develop as an independent investigator who can bridge the disciplines of computational biology and clinical research in vascular neurology. To pursue this goal, Dr Giles has assembled a mentoring team with expertise in translational transcriptomic analysis. Complementing them is an advisory team with expertise in computational biology and statistics, atherothrombosis and immunobiology. Acute ischemic stroke caused by thrombi occluding large cerebral vessels is associated with significant mortality and morbidity. Despite emergency revascularization, via intravenous thrombolysis and mechanical thrombectomy, poor neurologic outcomes remain common. Etiologies of thrombi include atherothrombosis and cardioembolism. A key challenge in stroke medicine is to identify the etiology of stroke thrombi, in order to more effectively prevent future strokes. Dr. Giles’s central hypothesis is that the cellular pathogenesis of stroke thrombi varies between clots of different etiologies, and that these differences can be identified via transcriptomic analysis of cells within acute thrombi and blood samples. We will test this hypothesis with transcriptomic analysis of cells comprising acute stroke thrombi and paired circulating blood cells. We will determine whether clots of different etiologies contain cells of different activation statuses and transcriptional programs (Aim 1). Further, we will test the hypothesis that blood cell gene activation within thrombi causing atheroembolic stroke are related to the clinical response to revascularization treatments in an assembled multi-center cohort of patients with stroke (Aim 2). The proposed research is significant because stroke due to large vessel occlusion causes substantial mortality and morbidity and requires new precision medicine approaches to improve the efficacy of revascularization therapies. Further, recurrent stroke continues to exert a significant burden, and new approaches are needed to diagnose stroke etiology. The proposed research is innovative because it combines advanced transcriptomic techniques to provide insight into mechanisms of different thrombus etiologies. Consistent with NINDS priorities to accelerate basic research findings towards patient use, this proposal will prepare Dr. Giles as an independent investigator who can develop new approaches for personalized, timely, and effective revascularization and preventive therapeutics to improve outcomes among patients with stroke.
