Aerobic Running Capacity QTL's and Cardiac Performance

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DESCRIPTION (provided by applicant): An aerobic exercise treadmill test is used clinically to assess cardiovascular fitness, cardiovascular reserves, and as a general test of overall health status. Our long-term goal is to identify genes associated with heritable differences in aerobic exercise capacity. We evaluated treadmill aerobic running capacity in 11 inbred strains and observed a 3-fold difference in aerobic running capacity between COP and DA strains and 2) a strong correlation (r=0.86) between aerobic running performance and isolated heart performance (Langendorff-Neely). Given this large differential in aerobic capacity, we propose to identify chromosomal regions containing genes responsible for differences in aerobic running capacity observed between COP and DA rats, confirm them by constructing congenic strains, and identify strong candidate genes using differential gene expression in conjunction with gene mapping. Hypothesis 1: Aerobic running capacity is a heritable polygenic trait. The 3-fold difference in aerobic exercise capacity between the COP and DA inbred strains of rats provides a suitable substrate to identify chromosomal regions containing the genes responsible for inherited differences in aerobic running capacity; i.e. aerobic running capacity Quantitative Trait Loci (QTLs). Hypothesis 2: Gene(s) underlying the observed aerobic running capacity QTLs may be differentially-expressed in key organs, such as the left ventricle. Gene(s) responsible for an aerobic running capacity QTLs effect should map to the chromosomal region carrying the particular QTL. Genes possessing these characteristics will be superior candidates as genes responsible for, at least in part, a specific aerobic exercise capacity QTL. Specific Aim 1: to identify chromosomal regions containing genes linked to strain differences in aerobic running capacity by interval mapping. We will genotype rats present in the tails of the distribution of the aerobic running capacity phenotype. Specific Aim 2: To produce novel congenic strains by introgressing chromosomal regions containing high (or low) aerobic capacity QTL allele(s) (SPECIFIC AIM 1) into the (low (or high)) capacity inbred rat strain. These congenic strains will be phenotyped using a treadmill stress test to confirm the presence of an aerobic running capacity QTL. Specific Aim 3: To identify genes differentially-expressed in (key organs of) rats differing in aerobic running capacity, i.e., the COP and DA strains. Differentially-expressed genes that map near aerobic running capacity QTLs will be superior candidates for the gene(s) responsible for specific aerobic running capacity QTL.