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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：
8762215
负责人：
Douglas Gould
金额：
$ 34.56万
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/8762215
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 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 Proteins Regulation Relative (related person)Reporting Research Proposals Risk Role Series Severities Signal Pathway Signal Transduction Signal Transduction Pathway Stroke Stroke prevention System Testing Therapeutic United States Vascular Diseases Vascular Endothelial Cell Work age related aged angiogenesis base cell type cerebrovascular cerebrovascular lesion disability effective therapy efficacy testing extracellular human disease in vivo juvenile animal member mouse model mutant novel paralogous gene pre-clinical prevent protein folding therapeutic target 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）：颅内出血（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。当它们影响到儿童和年轻人时尤其如此。出血性中风的有效治疗是有限的，因此预防脑出血对减少这种衰弱性疾病的影响至关重要。然而，预防性治疗通常需要了解脑出血的致病机制。遗传研究已经成功地确定了某些形式的脑出血的病因，然而，在确定大多数形式的心血管疾病的潜在原因方面，仍有巨大的未满足的需求。我们发现，IV型胶原α - 1 （COL4A1）突变可引起广谱的高渗透性脑血管疾病（cvd），包括围生卒中、先天性脑孔畸形、脑白质病、脑微出血、颅内动脉瘤和脑出血。除了多次报道COL4A1突变导致显性遗传性心血管疾病外，我们最近的数据表明，5-10%的散发性ICHs患者有COL4A1或其平行COL4A2突变。因此，根据美国心脏协会的估计，COL4A1和COL4A2的突变在美国每年可能导致多达12,000例自发性脑出血新病例，在全球范围内可能导致300,000例。在这里，我们使用新的CVD遗传模型来确定COL4A1在血管发育和维持中的不同作用。利用遗传、分子和生化方法，我们将直接测试COL4A1对正常血管发育至关重要的基本细胞信号通路的调节。最后，我们将使用新的临床前