Gene-Environment Interactions and Stroke Susceptibility

基因-环境相互作用和中风易感性

基本信息

批准号：
6797885
负责人：
MYRIAM FORNAGE
金额：
$ 42.16万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-30 至 2006-08-31
项目状态：
已结题

项目摘要

Stroke is the third leading cause of death in the United States and is frequently associated with long-term disability. The stroke-prone spontaneously hypertensive rat (SHRSP), which was developed by selective breeding from the spontaneously hypertensive rat (SHR), represents a suitable model of hypertension-associated stroke. Stroke occurrence is influenced by the complex interaction of multiple genes and environmental factors. The role of dietary sodium and potassium in modulating the onset of stroke has been well documented both in humans and animal models. In the SHRSP, diet high in sodium and low in potassium accelerates the development of stroke. In contrast, a high intake of potassium markedly protects against stroke occurrence, even though blood pressure levels remain unchanged. We have applied a gene expression profiling strategy using oligonucleotide micro-arrays to identify genes and gene pathways implicated in the development of stroke in this animal model. Because gene expression profiles uniquely and comprehensively reflect the complex and dynamic interaction of a defined set of genes with the environment, characterization of gene expression changes induced by dietary perturbations among inbred rat strains differing in their genetic propensity to develop stroke will provide clues on the mechanisms governing the interaction of stroke susceptibility genes with the dietary factors known to influence the disease process. The proposed application will focus on identifying stroke-susceptibility genes interacting with dietary salt intake to influence the initiation of stroke events in the SHRSP by comparing the gene expression profiles in the cortical regions of the brain of male SHRSPs and SHRs exposed to a regular vs. stroke- permissive diet. We will then identify genetic variants in these expressional candidate genes, as well as a panel of selected biological/positional candidate genes. We will assess the cosegregation of the genetic variants with stroke latency in the F2 progeny of SHRSP x SHR parental crosses. In addition, we will examine whether the relationship between genetic variants in candidate genes and variation in stroke latency in the F2 is modified by dietary factors. We will finally evaluate the potential relevance of a paradigm of stroke causation established in an experimental model to human disease. Specifically, we will characterize sequence variation within or near the human homologue of ten genes identified in this proposal and determine whether variation in these genes is associated with stroke incidence in a large population-based sample of individuals participating in the Atherosclerosis Risk in Communities (ARIC) study. We will also identify and characterize DNA variation in a panel of selected stroke-candidate human genes and test whether variation in these genes is associated with risk of developing a stroke in the ARIC sample.

中风是美国的第三大死亡原因，是经常与长期残疾有关。容易发生的自发性高血压大鼠（SHRSP），由选择性开发从自发性高血压大鼠（SHR）繁殖，代表合适的高血压相关中风的模型。中风的发生受多个基因和环境因素的复杂相互作用。角色调节中风开始时的饮食钠和钾在人类和动物模型中都有良好的文献记载。在SHRSP中，饮食高钠和低钾的低钾会加速中风的发展。在对比，高钾摄入量明显防止中风即使血压水平保持不变，也会发生。我们有使用寡核苷酸应用基因表达谱分析策略微阵列鉴定与发展有关的基因和基因途径该动物模型中的中风。因为基因表达独特地谱图全面反映定义集的复杂而动态的相互作用具有环境的基因，基因表达的表征变化由近交大鼠菌株的饮食扰动引起的诱导发展中风的遗传倾向将提供有关机制的线索管理中风易感基因与饮食的相互作用已知影响疾病过程的因素。拟议的申请将专注于识别与饮食盐相互作用的中风敏感性基因通过比较雄性大脑皮质区域的基因表达谱 SHRSP和SHR暴露于常规饮食与允许饮食。我们将然后确定这些表达候选基因中的遗传变异作为选定的生物/位置候选基因的小组。我们将评估 F2中遗传变异的遗传变体的cosegregation Shrsp X Shr shr far farthers杂交的后代。此外，我们将检查是否候选基因中的遗传变异与变异之间的关系 F2中的中风潜伏期通过饮食因素改变。我们终于会评估建立的中风因果关系的潜在相关性在人类疾病的实验模型中。具体来说，我们将表征确定的十个基因的人类同源物内或附近的序列变化在此提案中，并确定这些基因的变异是否相关在大量的个体样本中，中风发生率参与社区（ARIC）研究的动脉粥样硬化风险。我们将还可以识别并表征一组选定面板中的DNA变化中风缩合的人类基因并测试这些基因的变异是否为与在ARIC样本中发展中风的风险有关。