| Research Abstract |
Atherosclerotic diseases, which are also know as lifestyle related diseases, are a major cause of death worldwide and draw substantial attention in the public health. To clarify pathphysiological mechanisms underlying the clustering of multiple risk factors for atherosclerotic diseases, we have been focusing on a unique animal model, the spontaneously hypertensive rat (SHR), in which hypertension, dyslipidemia, impaired glucose tolerance, and hyper-insulinemia are concomitantly observed. By performing genome-wide screens in F2 progeny involving SHR, its stroke-prone substrain (SHRSP) and normotensive control, Wistar Kyoto rat, we have found susceptibility genes for hypertension, dyslipidemia, and impaired glucose tolerance on, at least, 14 different chromosomal regions. Towards the gene identification, we have developed consomic/congenic strains for each of the target chromosomal regions. Here, a consomic rat is defined to contain a single entire chromosome from another strain, donor s
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train, which is substituted onto a recipient strain. On the other hand, a congenic rat is defined to contain a small genetic region but is otherwise identical to the original recipient strain. Once a consomic strain is successfully developed, it allows for rapid creation of a congenic strain for positional cloning.
In parallel, we are performing DNA microarray analysis to capture responsible biological pathways and to understand the framework of gene-gene interplay, so-called genome network. Gene expression changes were systematically evaluated in the rat with and without intervention. We have so far conducted pharmacological (antihypertensive drugs, lipid lowering drug, and insulin sensitizing drug) and dietary (high fat and high salt diet) interventions. Five organs-brain, heart, kidney, liver and adipose tissue- were excised and total RNA extracted from each organ for DNA microarray (35K) analysis. Based on the positional and expression data, we are currently exploring the mechanisms leading to the impaired homeostasis in the body. Less
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