Upstream regulators of the prothrombotic state

描述(改编自申请人摘要)： 申请者将探索一种新的方法来研究血栓前病变。 使用一种独特的临床模型--PIAL研究人脑循环的状态 脑动静脉畸形(AVM)。此协作项目 包括哥伦比亚大学反洗钱研究小组和 杜克大学的遗传学。血栓形成的“下游”错乱 被确定为中风某些亚型的病因学，建议用于 导致脑血栓、血栓形成或出血的机制。这 协作项目将检查上游监管路径，从而 临床上有明显的血栓状态。我们假设脑动静脉畸形是自发的 出血是由于血管血栓形成，导致病灶破裂。这个 血栓前状态是由于转化生长因子-8和血管生成素/Tie-2信号的异常所致。 转化生长因子-B具有多种功能，包括维持血管壁完整性 以及正常凝血的一些方面。转化生长因子-β受体的胚系突变， Endoglin和ALK-1；在血管生成素受体Tie-2中引起孟德尔 引起各种血管异常的疾病，这些血管异常在 脑动静脉畸形的病理改变。受基因影响的血栓形成前状态 在动静脉畸形中是零星的。遗传多态在endoglin中的趋同性， 在疾病的自然病程中，ALK-I和Tie-2导致 血栓前状态的发展，因此导致出血 动静脉畸形的临床表现。 申请者提议使用一家大型银行，这两家银行都是未来存档的 收集DNA样本以确定基因的多态模式 与临床高度相关的endoglin、ALK-1和Tie-2基因 表现为动静脉畸形出血，因此处于血栓前状态。数据在 临床报告和DNA采集将在哥伦比亚大学进行。国家-- 杜克大学将进行最先进的遗传和生化研究。特定的 目的1.Endoglin基因中的三个序列多态是已知的，并将是 脑动静脉畸形患者的基因分型，比较出血患者 (相对血栓前状态)与那些出现其他模式的人，如 以及正常的人口控制。特定目标2.尽管基因组 ALK-I基因的结构是已知的，到目前为止还没有系统的 正常人群中该基因的序列变异分析。这个 申请者将在人群中鉴定ALK-I的序列变体，以及 在AVM患者中检测这些指标。具体目标3.申请者将决定 Tie-2基因的基因组结构，鉴定序列多态 基因，并在正常人群和动静脉畸形人群中检测这些基因。具体目标4. 申请者将研究体内体细胞突变的参与 Endoglin、ALK-1和Tie-2基因在内皮细胞中寻找杂合性缺失 从脑动静脉畸形中分离出来的。

DESCRIPTION (Adapted from Applicant's Abstract): The applicants will explore a novel approach to investigating prothrombotic states in the human cerebral circulation by using a unique clinical model-pial cerebral arteriovenous malformations (AVMs). This collaborative project includes the Columbia University AVM Study Group and the Department of Genetics at Duke University. "Downstream" derangements of thrombosis have been identified as a etiology for certain subtypes of stroke, proposed for mechanisms leading to brain embolism, thrombosis or hemorrhage. This collaborative project will examine upstream regulatory pathways that lead to a clinically-evident thrombotic state. We hypothesize that AVM spontaneous hemorrhage is due to vascular thrombosis, leading to nidus rupture. The prothrombotic state is due to abnormal TGF-8 and angiopoietin/Tie-2 signaling. TGF-B has multiple functions, including maintenance of vessel wall integrity and aspects of normal coagulation. Germline mutations in the TGF-B receptors, Endoglin and ALK-1; and in the Angiopoietin receptor Tie-2 cause Mendelian disorders that cause various vascular anomalies that show similarities in pathology to cerebral AVMs. The genetically-influenced, pro-thrombotic state in AVMs is sporadic. The convergence of genetic polymorphisms in endoglin, ALK- I and Tie-2 results in, over the natural history of the disease, the development of a pro-thrombotic state and therefore brings about a hemorrhagic AVM clinical presentation. The applicants propose to use a large bank of both archived prospectively collected DNA specimens to identify a pattern of polymorphisms in the endoglin, ALK- 1 and Tie-2 genes that are highly correlated with the clinical presentation of AVM hemorrhage and therefore a pro-thrombotic state. Data on clinical presentation and DNA collection will be performed at Columbia. State- of-the-art genetic and biochemical studies will be conducted at Duke. Specific Aim 1. Three sequence polymorphisms in the endoglin gene are known and will be genotyped in AVM patients, comparing patients who present with hemorrhage (relative pro-thrombotic state) vs. those who present with other modes, as well as normal population controls. Specific Aim 2. Although the genomic structure of the ALK- I gene is known, to date, there has been no systematic analysis of sequence variation of this gene in the normal population. The applicants will identify sequence variants of ALK- I in the population, and assay these in AVM patients. Specific Aim 3. The applicants will determine the genomic structure of the Tie-2 gene, identify sequence polymorphisms in the gene, and assay these in normal and AVM populations. Specific Aim 4. The applicants will investigate the involvement of somatic mutations within the Endoglin, ALK-1, and Tie-2 genes by looking for LOH in the endothelial cells isolated from cerebral AVMs.