PHENOGENOMICS AND TISSUE SPECIFIC ROLES OF THE SRC COACTIVATORS IN GEMMS AND GRPS

Baylor College Of Medicine, Houston TX

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Abstract

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