GENETIC STUDIES OF ANEURYSMAL SUBARACHNOID HEMORRHAGE

中风是第三大致死原因，也是成年人致残的首要原因。最近的研究强调了遗传因素在几种类型中风的病因中的重要性。特别是，遗传流行病学和分子遗传学研究支持遗传因素在家族性颅内动脉瘤(IAS)和 蛛网膜下腔出血(SAH)。这个以患者为中心的项目的总体目标是推进对家族性IAS和SAH的遗传因素的研究。主要的假设是 特定的突变或易感基因导致家族性IAS和SAH的发生。由于患有IAS或SAH的多个活体受累者的家庭很少，初步将采用候选基因方法。我们将根据弹性蛋白在血管完整性中的重要性以及先前的研究显示IAS和SAH患者中弹性蛋白、弹力酶和弹力酶抑制物的变化，重点介绍与弹性蛋白代谢有关的基因。当有足够的家庭资源时 确定后，将进行遗传连锁研究。家族性IA/SAH基因突变或易感基因的识别将极大地影响此类患者的治疗，并有助于高危无症状家庭成员的筛查和治疗。 这个项目的重点是以病人为中心的研究。首席调查员将参与IA/SAH家庭的诊断和确定。无症状高危 家庭成员将接受咨询，了解是否需要使用磁共振血管成像和CT血管成像等非侵入性技术对未破裂的IAS进行筛查。这个 基于实验室的研究将重点放在使用PCR、SSCP和DNA测序技术筛选候选基因上。这一研究项目与PI的背景和专业知识相结合，在临床和遗传学研究中提供了广泛的以患者为导向的指导机会。

Stroke is the third leading cause of death and the leading cause of disability among adults. Recent studies have highlighted the importance of genetic factors in the etiology of several types of stroke. In particular, genetic epidemiologic and molecular genetic studies support the importance of genetic factors in the pathogenesis of familial intracranial aneurysms (IAs) and subarachnoid hemorrhage (SAH). The overall goal of this patient-oriented project is to advance the study of genetic factors responsible for familial IAs and SAH. The primary hypothesis is that specific mutations or susceptibility loci contribute to the development of familial IAs and SAH. Due to the paucity of families with multiple living affecteds having IAs or SAH, a candidate gene approach will be utilized initially. We will focus on genes involved in the metabolism of elastin, based on its importance in vascular integrity and prior studies showing altered elastin, elastase, and elastase inhibitors in patients with IAs and SAH. When adequate family resources are ascertained, genetic linkage studies will be performed. The identification of mutations or genetic susceptibility loci for familial IA/SAH will greatly influence the care of such patients as well as aid the screening and treatment of at-risk asymptomatic family members. This project has a major focus on patient-oriented research. The principal investigator will be involved in the diagnosis and ascertainment of families with IA/SAH. Asymptomatic at-risk family members will be counseled about the need to undergo screening for unruptured IAs using non-invasive techniques such as magnetic resonance angiography and CT angiography. The laboratory based research will focus on screening candidate genes using PCR, SSCP and DNA sequencing techniques. This research project combined with the PI's background and expertise provide a wide range of patient-oriented mentorship opportunities in clinical and genetic research.