Investigating the extracellular matrix in vascular development and maintenance

描述（由申请人提供）：脑内出血（ICH）和出血性卒中是一种特别致命的卒中形式，也是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。出血性卒中的有效治疗是有限的，因此ICH预防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。我们已经发现IV型胶原α 1（COL 4A 1）的突变引起广泛的高度渗透性脑血管疾病（CVD），包括围产期中风、先天性脑穿通症、白质脑病、脑微出血、颅内动脉瘤和ICH。除了COL 4A 1突变导致显性遗传性CVD的多个报告外，我们最近的数据表明，5-10%的散发性ICH患者在COL 4A 1或其副产物COL 4A 2中存在突变。因此，根据美国心脏协会的估计，COL 4A 1和COL 4A 2的突变可能导致美国每年多达12，000例自发性ICH新发病例，全球有300，000例。在这里，我们使用新的CVD遗传模型来确定COL 4A 1在血管发育和维持中的不同作用。利用遗传、分子和生物化学方法，我们将直接测试COL 4A 1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 我们已经产生了人类CVD模型，以确定可能开发用于患者的治疗方法，并可能降低他们患衰弱或致命ICH的风险。

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.