A Mouse Model for Complex Human Diseases

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EXCEED THE SPACE PROVIDED. We propose to completethe developmentof a large series of recombinant inbred (RI) strains formed from the intercross of LG/J and SM/J mouse strains. These strains have already completed two-thirds of the generations needed to reach effective inbred status. We will also score a large number of polymorphic microsatellite markers in these strains to genetically characterize them for our own work and the work of others using the RI strain set. In additionto developing RI strains, we will maintain an advanced intercross (AI)strain. This strain was formed by random mating from the same F2 populationused in generating the RI strains. The combination of RI and AI strains from the same intercross will be a powerful resource for quantitative trait locus mapping for a wide variety of characters. We will test the RI strains for genetic variation in maternal effects on both neonatal and adult phenotypes using 40 reciprocal crosses between the RI strains and a standard inbred strain, C57BL/6J. In this design genetically different mothers give rise to genetically identical offspring so that reciprocal differences are due to genetic effects on the environment a mother provides for her offspring. In addition, we will test the "thrifty phenotype" hypothesis that states that pre- and neonatal environment affects risk for diseases (hypertension, diabetes, obesity, coronary artery disease, etc.) in adulthood. Poorly nourished neonates adapt to lownutrition levels in utero and soon after birth. This adaptation persists into adulthood so they are particularly susceptible to the deleterious effects of a high fat diet later in life. The offspring from the reciprocal crosses will receive either a high or a low fat diet after weaning. We will test whether animals subjected to relatively poor pre-and neonatal environments respond more strongly to the high fat diet. We will map quantitative trait loci for these genetic maternal effects and their interaction with diet. PERFORMANCE SITE ========================================Section End===========================================