Integrative Genomics of Stroke

描述（由申请人提供）： 中风是全球第三大死亡原因，也是导致严重残疾的主要原因。它是一种复杂的疾病，由许多不同的病理条件，包括动脉粥样硬化和高血压，因此受到多种遗传和环境因素的影响。了解中风的遗传基础将使我们更深入地了解其发病机制。作为一种复杂的疾病性状，中风易感性的遗传基础可以通过使用数量性状基因座分析来研究，以确定与之相关的DNA区域，在这个proposal中，我们的目的是研究脑梗死的易感性，在存在局灶性脑缺血小鼠通过一个综合应变调查。我们假设，在缺血的存在下，脑梗死的易感性在近交系小鼠中各不相同，并且这种表型变异在品系之间具有遗传基础。我们将对近交系表型进行计算机QTL作图（单倍型关联作图），以确定具有卒中易感基因的潜在染色体区域。我们将整合QTL结果与微阵列基因表达分析和其他生物信息学工具，以缩小QTL区域的选择中风易感性的候选基因。单基因分析将扩展到纳入概率基因网络。通过QTL定位预测的影响中风易感性的候选基因可以应用于人类研究，并最终导致各种脑血管疾病患者的脑保护的治疗和预测工具。 公共卫生相关性： 中风是一个主要的公共卫生负担。这个项目使用中风的小鼠模型来研究中风易感性的遗传基础。这将通过计算和生物信息学工具以及新兴的遗传学资源来实现。

DESCRIPTION (provided by applicant): Stroke is the third leading cause of mortality and the leading cause of severe disability worldwide. It is a complex disease that results from many different pathologic conditions including atherosclerosis and hypertension and is therefore affected by multiple genetic and environmental factors. Understanding the genetic basis of stroke will allow us to gain a deeper understanding of the mechanisms behind its pathogenesis. As a complex disease trait, the genetic basis of stroke susceptibility can be studied by using quantitative trait loci analysis to identify regions of DNA that are associated with it. In this proposal, we aim to study the susceptibility to cerebral infarction in the presence of focal cerebral ischemia in mice via an integrative strain survey. We hypothesize that susceptibility to cerebral infarction in the presence of ischemia vary among inbred strains of mice and that this phenotypic variability across strains has a genetic basis. We will perform in silico QTL mapping (haplotype association mapping) for inbred strain phenotypes to identify potential chromosomal regions with stroke susceptibility genes. We will integrate the QTL results with that of microarray gene expression analysis and other bioinformatics tools to narrow down the QTL regions for selection of candidate genes causing stroke susceptibility. The single gene analysis will be extended to incorporate probabilistic gene networks. The candidate genes which affect the vulnerability to stroke as predicted by the QTL mapping can be applied to human studies and ultimately lead to therapeutic and predictive tools for cerebral protection in patients with a variety of cerebrovascular diseases. PUBLIC HEALTH RELEVANCE: Stroke is a major public health burden. This project uses a mouse model of stroke to examine the genetic basis of stroke susceptibility. This will be accomplished via computational and bioinformatics tools together with the emerging genetics resources.