Stroke is the third leading cause of death in the United States and is frequently associated with long-term disability. We propose to apply a systematic strategy using oligonucleotide micro-array technology to identify genes involved in the initiation of stroke in two animal models: the stroke-prone spontaneously hypertensive rat (SHRSP) and the atherosclerosis-susceptible dog. We then propose to investigate the relevance of DNA sequence variation in the expressional candidate genes to susceptibility for human stroke in a large population-based study. We postulate that deviations from normal physiologic processes leading to stroke are accompanied by cellular and biochemical alterations which are reflected by changes in gene expression patterns in susceptible tissues. We further hypothesize that inherited DNA sequence variation in these same genes are at least partially responsible for interindividual variation in stroke susceptibility. These hypotheses will be addressed in four specific aims. In the first aim, we propose to apply the newly developed oligonucleotide micro-array technology to identify expressional candidate genes contributing to stroke occurrence in the SHRSP, a hypertension-related model of human stroke. The expression level of more than 24,000 gene transcripts will be simultaneously monitored in brain tissue and compared between the SHR and SHRSP rat. In the second aim, we propose to apply a similar but more focused technology to identify expressional candidate genes contributing to stroke in the atherosclerosis- susceptible dog, a unique atherosclerosis-related model of human stroke. In the last two aims, we will evaluate the potential relevance to human disease of the information obtained from the two animal models. Specifically, we will characterize sequence variation within or near the human homologue of 20 genes 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. In the third aim, we will use direct DNA re- sequencing to identify variation within or near the human homologue of 10 expressional candidate genes identified in aims 1 and 2. We will also identify sequence variation in the coding and 5' regulatory regions of 10 additional biological candidate genes. In the fourth aim, we will determine whether DNA sequence variation in the genes identified in Aim 3 contributes to interindividual variation in risk of developing stroke in a well characterized sample of Caucasians and African-Americans. These studies represent a first step in unraveling the genetic architecture of stroke susceptibility in the population-at-large. This collaborative effort is novel for its ability to translate unique animal model research findings to the human condition.
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