Pathophysiology of a Genetic Vascular Disease

遗传性血管疾病的病理生理学

• 批准号: 10027242
• 负责人: KEVIN J WHITEHEAD
• 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 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10027242
• 关键词: Acute; Adhesions; Adult; Affect; Americas; Animal Model; Antioxidants; Binding; Biological; Biological Assay; Biological Testing; 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; Drug Screening; Electron Spin Resonance Spectroscopy; Embryo; Endothelial Cells; Endothelium; Environment; Expression Profiling; Family; Fibroblasts; Fluorescent Dyes; Formulation; Foundations; Functional disorder; Future; Genes; Genetic; Genetic Transcription; Genotype; Growth; Hemorrhage; Human; Impairment; In Vitro; Inflammation; Inherited; Ischemic Stroke; Knock-out; Lesion; Magnetic Resonance Imaging; Measures; Mediating; Mediator of activation protein; Mitochondria; Molecular; 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; Pathogenicity; Pathology; Pathway interactions; Permeability; Persons; Phenotype; Platelet aggregation; Play; Population; Prevention; Prevention therapy; 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; Tissues; 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; 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 candidate; therapeutic target; transcription factor; translation to humans; 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.

 描述（由申请人提供）： 中风是美国第四大死亡原因，也是发病的主要原因，尽管在预防和治疗缺血性中风方面取得了重大进展，但对出血性中风的机制和预防知之甚少。脑海绵状血管畸形 (CCM)，用于研究出血性中风和脑血管疾病的机制。CCM 的特点是慢性血管渗漏导致炎症，随后急性出血导致出血。这项研究将直接应用于估计患有 CCM 的超过 100,000 名退伍军人，并且随着我们的结论更广泛地应用于脑血管疾病，它具有影响数百万退伍军人的巨大潜力。 CCM 病例的一个重要子集是家族性和中风。代表出血性中风的遗传原因。在这些与 CCM 相关的家族中已鉴定出三个独立的基因（KRIT1、OSM 和 PDCD10），这些基因是内皮细胞中必需的。正常血管发育、内皮细胞细胞骨架结构和内皮屏障功能尤其是，KRIT1 和 OSM 的缺失导致胚胎、成年小鼠和内皮细胞培养物中非常相似的表型。作为细胞质蛋白复合物的一部分，参与支架小 GTP 酶，参与细胞对应激的反应并控制细胞骨架和屏障功能，这是一种主要的内皮信号传导。级联涉及由一氧化氮合酶 (eNOS) 的内皮亚型产生的一氧化氮 (NO)，以诱导平滑肌松弛、防止血小板聚集、限制平滑肌增殖并抑制白细胞粘附。成纤维细胞中 KRIT1 的缺失导致活性氧增加。然而，ROS 的增加是否因 KRIT1、OSM 或 CCM 的突变而在 CCM 的发病机制中发挥作用。重要的是，一些证据表明与每个 CCM 基因功能丧失相关的失调信号通路可能不同，因此，我们认为 CCM 蛋白丧失导致的 ROS 增加是导致这种情况的关键因素。 CCM 中的血管病理学可以通过清除过量的超氧化物来挽救，并且作为 CCM 疾病的下游常见致病机制。这项工作将测试一个重要的功能假设，并阐明出血性中风综合征的一个有前途的潜在治疗靶点。此外，这项工作有可能在不久的将来为人体临床试验提供从实验室到临床转化的路线图，为未来检查超氧化物清除剂在治疗和预防其他脑血管疾病中的应用奠定基础。该提案对于估计患有 CCM 疾病的超过 100,000 名退伍军人具有直接转化潜力，并且将为更广泛影响退伍军人群体的疾病奠定基础。

项目成果

Clinical presentation and treatment paradigms in patients with hereditary hemorrhagic telangiectasia and spinal vascular malformations.

遗传性出血性毛细血管扩张症和脊髓血管畸形患者的临床表现和治疗范例。

• DOI: 10.1016/j.jocn.2018.01.010
• 发表时间: 2018
• 期刊: Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia
• 作者: Eli,Ilyas;Gamboa,NicholasT;Joyce,EvanJ;Park,MinS;Taussky,Philipp;Schmidt,RichardH;Couldwell,WilliamT;McDonald,Jamie;Whitehead,KevinJ;Kalani,MYasharS
• 通讯作者: Kalani,MYasharS