Investigating the extracellular matrix in vascular development and maintenance

研究细胞外基质在血管发育和维持中的作用

基本信息

批准号：
9087349
负责人：
Douglas Gould
金额：
$ 34.67万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9087349
关键词：
Acids Address Affect American Heart Association Basement membrane Binding Biochemical Blood Vessels Brain hemorrhage Caenorhabditis elegans Cause of Death Cells Cerebral hemisphere hemorrhage Cerebrovascular Disorders Cerebrum Cessation of life Chemicals Child Code Collagen Type IV Data Defect Deposition Development Disease Etiology Event Extracellular Matrix FDA approved Gene Expression Profiling Genes Genetic Genetic Models Genetic study Health Homeostasis Human In Vitro Inherited Intervention Intracranial Aneurysm Lead Lesion Leukoencephalopathy Maintenance Membrane Proteins Molecular Molecular Chaperones Molecular Genetics Mus Mutant Strains Mice Mutation Pathogenesis Pathology Pathway interactions Patients Pericytes Perinatal Perinatal subependymal hemorrhage Play Pre-Clinical Model Prevention Preventive therapy Proteins Regulation Reporting Research Proposals Risk Role Series Severities Signal Pathway Signal Transduction Signal Transduction Pathway Stroke Stroke prevention System Testing Therapeutic Transforming Growth Factor beta United States Vascular Diseases Vascular Endothelial Cell Work age related aged angiogenesis base brain endothelial cell cell type cerebral microbleeds cerebrovascular cerebrovascular lesion conditional mutant disability effective therapy efficacy testing extracellular human disease in vivo juvenile animal member mouse model mutant novel paralogous gene patient subsets pre-clinical prevent protein folding targeted treatment young adult

项目摘要

DESCRIPTION (provided by applicant): Intracerebral hemorrhages (ICH) and hemorrhagic stroke are a particularly fatal form of stroke and an important cause of long-term disability. This is especially true when they affect children and young adults. Effective treatments for hemorrhagic stroke are limited, and so ICH prevention is paramount for reducing the impact of this debilitating condition. However, preventative therapies often require an understanding of the pathogenic mechanism underlying ICH. Genetic studies have successfully defined the etiologies of some forms of ICH, however there is still a tremendous unmet need in determining the underlying causes of most forms of CVD. We have discovered that mutations in type IV collagen alpha 1 (COL4A1) cause a broad spectrum of highly penetrant cerebrovascular diseases (CVDs), including peri-natal stroke, congenital porencephaly, leukoencephalopathy, cerebral microbleeds, intracranial aneurysm, and ICH. In addition to multiple reports of COL4A1 mutations causing dominantly inherited CVD, our recent data suggest that 5-10% of patients suffering from sporadic ICHs have mutations in COL4A1 or its paralog COL4A2. Thus, according to American Heart Association estimates, mutations in COL4A1 and COL4A2 could cause up to 12,000 new cases of spontaneous ICH in the United States each year and 300,000 cases worldwide. Here we use novel genetic models of CVD to identify distinct roles for COL4A1 in vascular development and maintenance. Using genetic, molecular, and biochemical approaches we will directly test the regulation by COL4A1 of fundamental cell- signaling pathways that are critical for normal vascular development. Finally, we will use novel pre-clinical models of human CVD that we have generated to identify therapeutics that may be developed for use in patients and that may reduce their risk of suffering debilitating or fatal ICHs.

描述（由申请人提供）：脑出血（ICH）和出血性中风是一种特别致命的中风形式，也是导致长期残疾的重要原因。这当它们影响儿童和年轻人时尤其如此。出血性中风的有效治疗方法有限，因此预防脑出血对于减少这种使人衰弱的疾病的影响至关重要。然而，预防性治疗通常需要了解 ICH 的致病机制。遗传学研究已经成功地确定了某些形式的 ICH 的病因，但是在确定大多数形式的 CVD 的根本原因方面仍然存在巨大的未满足的需求。我们发现 IV 型胶原蛋白 α 1 (COL4A1) 的突变会导致多种高渗透性脑血管疾病 (CVD)，包括围产期中风、先天性无脑畸形、白质脑病、脑微出血、颅内动脉瘤和脑出血。除了 COL4A1 突变导致显性遗传性 CVD 的多项报道外，我们最近的数据表明，5-10% 的散发性 ICH 患者存在 COL4A1 或其旁系同源物 COL4A2 突变。因此，根据美国心脏协会的估计，COL4A1 和 COL4A2 的突变每年可能在美国导致多达 12,000 例自发性脑出血新病例，在全球范围内导致 300,000 例。在这里，我们使用新型 CVD 遗传模型来确定 COL4A1 在血管发育和维护中的独特作用。我们将使用遗传、分子和生化方法直接测试 COL4A1 对基本细胞信号传导途径的调节作用，这对正常血管发育至关重要。最后，我们将使用新颖的临床前我们生成的人类心血管疾病模型是为了确定可以开发用于患者的治疗方法，并可以降低他们遭受衰弱或致命的脑出血的风险。