Gene Discovery for Cerebral Cavernous Malformations

描述(申请人提供)：脑海绵状畸形 大脑的(CCMS)是血管病变，高达0.4%的 一般人群，常伴有癫痫、偏头痛、 出血性中风和其他神经后果。这些损害可能会发生 零星的，或作为常染色体显性性状。我们小组最近 发现了CCM1基因，它负责大多数家族性 CCMS和主要是西班牙裔家庭形式的CCM的原因 人口(Sahu等人，1999年)。随着CCM1基因的发现，我们有了 对这种“家族性中风”的病理有了重要的洞察力。 还有另外两个CCM基因有待鉴定，CCM2在 染色体7p和3q上的CCM3。我们将利用我们之前的经验 一种成功的位置克隆方法，它使用了强大的 成绩单识别的计算方法 测序的位置候选者。我们相信，这些资源将拥有 和我们已经建立的方法将使我们能够识别 CCM2和CCM3的基因。在确定了与CCM2和CCM2相关的基因后 CCM3，我们将开始研究它们在细胞中的作用，特别是， 它们在CCM病理生理学中的作用。这些类型的实验包括 胚胎和成体细胞内的总蛋白质表达模式 间隔室定位研究，以及使用 酵母菌双杂交筛选。这些数据将为分子/细胞 框架，在此框架中启动对这些蛋白质的更详细分析 未来的建议。我们的最终目标是帮助理解 不同形式的家族性精神障碍的基本机制 神经血管疾病。模型的可用性，其中主要基因 确定词已经被明确地识别出来，将大大加快 探寻“家族性卒中”的基本机制并寻求更好的方法 对神经血管疾病的一般认识。

DESCRIPTION (provided by the applicant): Cerebral cavernous malformations (CCMs) of the brain are vascular lesions, which are present in up to 0.4% of the general population and often are accompanied by seizures, migraine, hemorrhagic stroke and other neurological outcomes. These lesions can occur sporadically, or as an autosomal dominant trait. Our group has recently identified the CCM1 gene, which is responsible for the majority of all familial CCMs and principally the cause for the familial form of CCMs in the Hispanic population (Sahoo et al., 1999). With the discovery of the CCM1 gene, we have developed a significant insight into the pathology of this "familial stroke." There are two additional CCM genes that remain to be identified, CCM2 on chromosome 7p and CCM3 on chromosome 3q. We will utilize our previously successful approach for positional cloning, which employs a strong computational approach to transcript identification in order to identify positional candidates for sequencing. We believe that the resources will have accumulated and the approach we have established will allow us to identify the genes for CCM2 and CCM3. After identifying the genes responsible for CCM2 and CCM3, we will begin to investigate their role in the cell, and in particular, their role in the pathophysiology of CCM. These types of experiments include overall protein expression patterns in the embryo and the adult, cellular compartment localization studies, and a search for interacting proteins using the yeast two-hybrid screen. These data will provide the molecular/cellular framework from which to launch a more detailed analysis of these proteins in a future proposal. Our ultimate objective is to aid in understanding the fundamental mechanisms responsible for different forms of familial neurovascular disease. The availability of a model, where the primary genetic determinates have been identified unambiguously, will greatly expedite the search for the basic mechanisms involved in "familial stroke" and to a better understanding of neurovascular disease, in general.