Dysregulation of cardiac metabolism is associated with obesity, type 2 diabetes and heart failure. Deciphering the gene regulatory mechanisms that control cardiac energy metabolism offers great promise for the development of more precise and effective approaches to prevent and treat heart disease. Recently, we discovered that MED13, a subunit of the kinase submodule of the Mediator complex, acts in the heart to control systemic energy homeostasis in mice. Elevated cardiac expression of MED13 confers a lean phenotype and resistance to obesity, whereas cardiac deletion of MED13 enhances susceptibility to obesity and insulin resistance. To further explore the role of Mediator in metabolism and growth, we are studying the role of MED12, another subunit of the kinase submodule of the Mediator complex, in cardiac muscle development and metabolism. The overall goal of this proposal is to provide a deeper understanding of the mechanisms whereby MED12 regulates metabolism, energy homeostasis, heart disease, and muscle development and function. Our general strategy is to use the sophisticated genetic and molecular tools available to mouse models to study MED12 function in vivo. We will take advantage of both a conditional cardiac MED12 knockout line, and inducible cardiac MED12 knockout line that we have generated to genetically investigate the molecular mechanism by which MED12 controls heart development and function. These studies will involve detailed analysis of cardiac growth, gene expression, and changes in metabolism. We anticipate these efforts will elucidate further the function of MED12 in development and possibly its role in metabolic homeostasis.
The Mediator Complex subunit Med12 has been linked with neurological diseases such as X-linked dominant mental retardation syndromes, as well as numerous different types of cancers. The goal of this proposal is to characterize an unexplored function of MED12 in cardiac tissue. We anticipate this study will provide insights into the function of human MED12 and thus promote the development of therapeutics and diagnostics for MED12-related diseases, in addition to linking the gene to cardiac disease and energy homeostasis.
