Genetic and Mechanistic Study of Cerebral Small Vessel Disease

摘要 在美国，每19例死亡中就有一例是中风造成的， 2009年，中风为3120亿美元（而所有癌症为2280亿美元）。脑小血管 疾病（SVD）占中风的30%，是与年龄相关的认知能力下降的主要原因， 残疾。编码IV型胶原α 1（COL4A1）的基因的罕见突变导致遗传性SVD 包括脑白质疏松症、皮质下微出血、脑穿通、颅内动脉瘤、血管周围扩大 腔隙性脑梗塞和出血性中风常见的COL4A1变体与 颅内动脉瘤，动脉钙化，脑深部血管，腔隙性缺血性卒中，减少 白色物体积和白质脑病。COL4A1突变如何导致SVD尚不清楚， 代表了我们现有知识中的一个重大缺口。这一建议体现了一种综合和全面的 了解SVD发病机制的方法。我们多元化团队的目标是确定新的SVD病因 以及可以靶向预防、延迟或减少SVD损伤的致病机制。我们的具体 重点是COL4A1突变的细胞内和细胞外后果，然而，我们也有 有可能识别新的SVD子类，并打破不相关的研究领域。

Abstract Strokes account for one out of every 19 deaths in the United States and the cost for cardiovascular disease and strokes in 2009 was $312 billion dollars (compared to $228 billion for all cancers). Cerebral small vessel diseases (SVD) account for up to 30% of strokes and are a leading cause of age-related cognitive decline and disability. Rare mutations in the genes encoding collagen type IV alpha 1 (COL4A1) cause inherited SVD including leukoaraiosis, subcortical microbleeds, porencephaly, intracranial aneurysms, enlarged perivascular spaces, lacunar infarctions and hemorrhagic strokes. Common COL4A1 variants have been associated intracranial aneurysms, arterial calcification, deep intracerebral hemorrhages, lacunar ischemic stroke, reduced white matter volume and leukoencephalopathy. How COL4A1 mutations cause SVD is unknown and represents a significant gap in our current knowledge. This proposal represents an integrated and holistic approach to understand SVD pathogenesis. The goal of our diverse team is to identify novel SVD etiologies and pathogenic mechanisms that can be targeted to prevent, delay or reduce damage from SVD. Our specific focus is on the intracellular and extracellular consequences of COL4A1 mutations, yet, we also have the potential to identity novel SVD subclasses and break open unrelated areas of research.