By modulating the activity of many transcription factors, coregulators have a profound influence upon cellular metabolic pathways. The phenotypic characterization of the various SRC -/- animals, generated by classical germline knock-out (KO) strategies in the previous PPG, has shown that the steroid receptor coactivators (SRCs) have a major impact on metabolic homeostasis and are thus potential contributors to the metabolic syndrome. Most striking was that energetic efficiency is increased in SRC-2-/- and SRC-3-/- mice, protecting them from the development of obesity and associated metabolic problems. To ascertain the tissue-specific contributions of SRCs and the mechanisms underlying these metabolic abnormalities, which are typically compensated for in germline KOs, we now propose to generate and characterize genetically engineered mouse models (GEMMs) in which somatic mutations in the different SRC genes can be introduced in white adipose tissue and skeletal muscle in a temporally controlled fashion. We focused on these tissues, since they are prototypical tissues either storing or combusting energy. In parallel, we propose to study mouse models with natural genetic variation in SRC-X expression, such as that found in genetic reference populations (GRPs) like the 38 BxD recombinant inbred (Rl) mouse lines. As the goal is to progress towards the treatment and prevention of metabolic diseases in humans, GEMMs, in contrast to GRPs, are optimized to study the actions of isolated genetic loci and are thus insufficient to characterize polygenic networks and genetic and environmental interactions that cause common metabolic diseases. We therefore also will perform a detaHed metabolic analysis combined with an in-depth whole genome gene expression analysis of white adipose tissue and skeletal muscle of the 38 BxD Rl lines. Finally, we will integrate the data using directional genetic strategies in GEMMs with global analyses of GRPs, to identify regulatory gene networks in which SRCs operate in white adipose tissue and skeletal muscle. This will allow us to merge the benefits of the clear cut results of single gene perturbations with the subtle alterations that result from innumerable allelic variants.
Our specific aims are (1) generation and phenotypic analysis of spatially- and temporallycontrolled SRC mutant mouse lines and (2) phenogenomic characterization of a BxD panel of Rl mice which due to inherent natural genetic/polygenetic variation display a continuum of SRC-X expression levels.
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