| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2001: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2000: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Research Abstract |
In the present study, we explored quantitative trait loci (QTLs) for atherosclerotic phenotypes in F2 progeny derived from the spontaneously hypertensive rat (SHR), stroke-prone SHR (SHRSP), and Wistar Kyoto rat (WKY). First, we identified more than 7 QTLs for blood pressure (BP) and 3 QTLs for serum cholesterol levels in genome-wide screens using 578 F2 rats derived from SHRSP and WKY. Subsequently, in genome-wide screens using 326 F2 rats derived from SHR and WKY, we identified a number of linkages to metabolic traits, such as serum triglycerides, insulin, glucose levels, and insulin resistance phenotypes characterized in vitro, all of which were considered to be associated with the multiple risk factor syndrome in humans. Some of the chromosomal regions thus identified appeared to be linked to more than one traits. For example, a region on rat chromosome 9 was significantly linked to serum glucose levels and BP, while a region on rat chromosome 15 was significantly linked to serum cholesterol levels and BP.
Based on the results, we chose 8 chromosomal regions to further investigate QTLs by developing congenic rat strains. Among them, it is assumed that a chromosome-1 region would harbor a "major" QTL (or QTLs) for BP in SHR strains as well as for the propensity of stroke and renal damage. As for this chromosome-1 congenic rat strain, where a small fragment was trapped from WKY onto SHRSP background, we constructed comparative genetic maps between rats, mice, and humans, and radiation hybrid maps. At present, we have succeeded in the development of congenic lines harboring as small as a 8-cM fragment, which shows 22 mmHg decrease in BP, 15% decrease in heart weight, and significant reduction of the stroke incidence as compared to parental SHRSP strains.
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