RESOURCE FOR RAT GENETIC MODELS OF AEROBIC CAPACITY

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The ability of cells to utilize oxygen as an electron acceptor (aerobic metabolism) for energy transfer defines a major aspect of our biology at all levels of organization. We developed rat models for low and high intrinsic (untrained) aerobic capacity and have had numerous requests for samples of these rats to study. These models were started in 1996 from a founder population of 168 N:NIH rats. Divergent artificial selective breeding was applied to create low and high lines that contrast for aerobic treadmill running capacity. After 10 generations of selection we recorded a 317% difference in aerobic capacity between the low and high lines. We request the resources to create, phenotype, and provide these animals, their tissues, and parental DNA for others to study. Appended to this grant are requests from 23 investigators to use these models to answer previously unexplorable questions such as: 1) What phenotypes are associated exclusively with intrinsic (i.e., untrained) aerobic capacity? 2) Will differential expression analysis reveal previously unsuspected pathways that contribute to intrinsic aerobic capacity? 3) To what extent does the positive association between aerobic capacity and health accrue from intrinsic capacity relative to trained capacity? 4) What health-related traits correlate with intrinsic capacity, such as longevity or resistance to diabetes mellitus, hypertension, heart disease, obesity, cancer, or infective agents? We present here as an example, detailed plans to provide our models for initial collaborations with three experienced teams: 1) Drs. Rail and Hansen will establish a bank of cryopreserved embryos and store them in a low-temperature repository. 2) Drs. Wagner and Gonzales will measure the conductance properties of each step of the 02 transport path from the air to the mitochondria of skeletal muscle. 3) Drs. Bouchard and Rankinen will evaluate differential messenger RNA expression using large-scale micro-array technology in 11 tissues. Subsequently, we propose to escalate our plan in order to provide low and high aerobic rats as a resource for a minimum of 43 major studies over five years. [Since last submission we have: 1) acquired more space for our rat colony quarantine barrier area to assure adequacy for growth, and 2) upgraded our sentinel surveillance program to substantially increase the monitoring of the health status of our colony.]