Pathophysiology of a Genetic Vascular Disease

遗传性血管疾病的病理生理学

• 批准号: 8923096
• 负责人: DEAN Yaw LI
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-10-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8923096
• 关键词: Acute; Adhesions; Adult; Affect; Americas; Animal Model; Antioxidants; Binding; Biological Assay; Blood Vessels; Brain hemorrhage; CCM1 gene; Cause of Death; Cell Culture Techniques; Cells; Cellular Morphology; Cerebrovascular Disorders; Chronic; Clinical; Clinical Trials; Complex; Cytoplasmic Protein; Cytoskeleton; Defect; Dermal; Development; Diagnosis; Disease; Electron Spin Resonance Spectroscopy; Embryo; Endothelial Cells; Endothelium; Environment; Family; Fibroblasts; Fluorescent Dyes; Formulation; Foundations; Functional disorder; Future; Genes; Genetic; Genotype; Growth; Hemorrhage; Human; Impairment; In Vitro; Inflammation; Inherited; Ischemic Stroke; Knock-out; Lesion; Leukocytes; Magnetic Resonance Imaging; Measures; Mediating; Mediator of activation protein; Mitochondria; Molecular; Molecular Profiling; Monomeric GTP-Binding Proteins; Morbidity - disease rate; Mus; Muscle relaxation phase; Mutation; Neuraxis; Nitric Oxide; Nitric Oxide Synthase; OSM gene; Oxidative Stress; Oxidative Stress Pathway; Pathogenesis; Pathology; Pathway interactions; Permeability; Persons; Phenotype; Platelet aggregation; Play; Population; Preclinical Drug Evaluation; Prevention; Protein Family; Protein Isoforms; Proteins; Reactive Oxygen Species; Recording of previous events; Reperfusion Injury; Reporting; Research; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Smooth Muscle; Specificity; Stress; Stroke; Structure; Superoxide Dismutase; Superoxides; Syndrome; System; Testing; Therapeutic; Tissues; Translations; United States; Vascular Diseases; Vasodilation; Veterans; Work; bench to bedside; catalase; catalase-polyethylene glycol; cell type; cerebral artery; cerebral cavernous malformations; cerebrovascular; chromatin immunoprecipitation; direct application; disability; efficacy testing; endothelial dysfunction; forkhead protein; improved; in vivo; insight; loss of function; malformation; mortality; mouse model; mutant; novel therapeutics; overexpression; prevent; public health relevance; response; scaffold; targeted agent; tempol; therapeutic target; transcription factor; treatment strategy

 DESCRIPTION (provided by applicant): Stroke is the fourth leading cause of mortality and a major cause of morbidity in the United States. Despite significant progress in the prevention and treatment of ischemic stroke, less is known about mechanisms and prevention of hemorrhagic stroke. We will use a hereditary stroke syndrome, Cerebral Cavernous Malformation (CCM), to study mechanisms underlying hemorrhagic stroke and cerebrovascular disease. CCM is characterized by chronic vascular leak leading to inflammation and by subsequent acute bleeding resulting in hemorrhagic stroke. This study will have direct and immediate application to the more than 100,000 veterans estimated to have CCM, and has significant potential to affect millions of veteran as our conclusions are applied more broadly to cerebrovascular disease. A significant subset of CCM cases is familial and represents a genetic cause for hemorrhagic stroke. Three separate genes have been identified in these families associated with CCM (KRIT1, OSM and PDCD10). These widely expressed genes are required in the endothelium for normal vascular development, endothelial cell cytoskeletal structure, and endothelial barrier function. In particular, the loss f KRIT1 and OSM results in very similar phenotypes in embryos, adult mice, and endothelial cell culture. Both KRIT1 and OSM have been found to bind each other as part of a complex of cytoplasmic proteins involved in scaffolding small GTPases involved in the cellular response to stress and controlling the cellular cytoskeleton and barrier function. A major endothelial signaling cascade involves nitric oxide (NO) produced by an endothelial isoform of nitric oxide synthase (eNOS) to induce smooth muscle relaxation, prevent platelet aggregation, limit smooth muscle proliferation, and inhibit leucocyte adhesion. The loss of KRIT1 in fibroblasts results in increased reactive oxygen species (ROS). However, whether increased ROS plays a role in the pathogenesis of CCM due to mutations in KRIT1, OSM, or PDCD10 has not been established. Importantly, some evidence suggests that the dysregulated signaling pathways associated with loss of function of each CCM gene may be different. Therefore, we hypothesize that increased ROS as a result of the loss of CCM proteins is a key contributor to vascular pathology in CCM, which can be rescued by scavenging excess superoxide, and serves as the downstream common pathogenic mechanism of CCM disease. This work will test an important functional hypothesis and clarify a promising potential therapeutic target in a hemorrhagic stroke syndrome and has the potential to provide a roadmap for bench-to-bedside translation to human clinical trials in the near future. Further, this work may serve as the foundation for future examinations of the use of superoxide scavengers in the treatment and prevention of other cerebrovascular disease. This proposal has both immediate translational potential for more than 100,000 veterans estimated to have CCM disease, and will underlie additional progress for diseases more broadly affecting the Veterans population.