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Vascular Pannexin 1 in Ischemic Stroke

缺血性中风中的血管 Pannexin 1

基本信息

批准号：
10091702
负责人：
Miranda E Good
金额：
$ 24.9万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10091702
关键词：
Academia Acute Adhesions Area Arteries Blood Vessels Blood flow Bone Marrow Transplantation Cell Adhesion Cells Cerebral Ischemia Cerebrovascular Circulation Cerebrovascular system Cerebrum Cessation of life Data Development Disease Emigrations Endothelial Cells Endothelium Etiology Experimental Designs Flow Cytometry Fostering Foundations Future Genetic Goals Image Infarction Inflammation Inflammatory Injury Integrins Intervention Ischemia Ischemic Stroke Knockout Mice Knowledge Lead Leukocytes Mentors Mentorship Mesenteric Arteries Morbidity - disease rate Mus Neurologic Deficit Nucleotides Obstruction Peripheral Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Play Preparation Process Protein Isoforms Proteins Purinoceptor Receptor Signaling Recovery Regulation Reperfusion Injury Reperfusion Therapy Research Research Personnel Role Severities Signal Transduction Stroke TNF gene Techniques Testing Therapeutic Intervention Thrombolytic Therapy Time Tissues Training Transgenic Mice Venous Work autocrine brain endothelial cell career development cerebral artery cerebral vein cost estimate experience experimental study improved in vivo in vivo imaging insight intravital microscopy ischemic injury mechanotransduction mortality new therapeutic target novel overexpression post stroke programs purinoceptor P2Y4 receptor response skills stroke outcome stroke patient targeted treatment therapeutic target venule

项目摘要

|| PROJECT SUMMARY/ABSTRACT Ischemic stroke is a significant disease that can lead to neurological deficits or death; however, only one pharmacological intervention drug is available and it predominately aims to eliminate the physical occlusion within the blood vessel. To explore potential therapeutic targets to improve recovery following an ischemic stroke, we began examining the role of Panx1 channels, which activate downstream purinergic receptors, within the cerebral vasculature. I have recently shown that deletion of endothelial Panx1 profoundly improves post-cerebral ischemia/reperfusion infarct volume. However, endothelial Panx1 could significant contribute to both arterial and venous endothelial functions. In this application, we demonstrate that arterial myogenic tone development (arterial), and inflammation of leukocytes following an ischemic stroke (venous), are significantly decreased in mice lacking endothelial Panx1. This application tests the hypothesis that endothelial Panx1 contributes to the development of ischemic stroke injury through both regulation of cerebral arterial myogenic tone and regulation of leukocyte adhesion and emigration in cerebral venous endothelial cells. Our preliminary data suggest that Panx1 activation during myogenic tone development is regulated through interaction with b3 integrins. Whereas, in cerebral veins, I find leukocyte adhesion in cerebral venules following an ischemic stroke is regulated through Panx1 channel function. These studies will provide insight into the differential roles and regulation of Panx1 within arterial and venous cerebral endothelial cells, their contribution to the etiology of ischemic stroke injury, and lay the foundation for future identification of therapeutic interventions for ischemic stroke patients. During the mentored phase of this application, I will develop novel transgenic mice to evaluate the overexpression of endothelial Panx1 and obtain necessary skills to evaluate the functional consequence of Panx1-b3 interaction and image cerebral inflammation following an ischemic stroke using in vivo intravital microscopy techniques. I will continue my professional and scientific development in preparation for the independent phase with continuous guidance from my mentoring committee. During the independent phase, I will develop a novel transgenic mouse that will delete or overexpress Panx1 specifically within arterial endothelial cells and determine the role of arterial verse venous endothelial Panx1 during an ischemic stroke. In addition, I will establish the downstream purinergic signaling involved in Panx1-dependent leukocyte adhesion, by in vivo imaging of cerebral venules, and emigration, using flow cytometry, and its impact of determining the severity of an ischemic stroke. This project will foster my continued scientific and professional training and facilitate my establishing an independent research program in academia.

||项目摘要/摘要