Metabolic diseases associated with aberrant metabolism of carbohydrates and lipids are the cause of significant morbidity and mortality in older people in Western Society. Several members of the nuclear receptor superfamily regulate the expression of key genes involved in regulation of carbohydrate and lipid metabolism in response to their ligands, which include fatty acids, bile acids, cholesterol metabolites, steroid hormones, and lipophilic vitamin derivatives. Recently, the ligand for a pair of related orphan nuclear hormone receptors that regulate lipid metabolism, rev-erb1 and rev-erb2, was identified. The long term objective is to determine the role of this ligand, the porphyrin heme, in regulation of the activity of the rev-erbs. Our organizing hypothesis is: heme is a key ligand regulating rev-erb1/2 function in regulation of genes controlling lipid metabolism and differentiation by modulating the receptors' affinity for corepressors. The hypothesis will be tested in the following specific aims:
Specific Aim 1 will determine the effect of heme on regulation of transcription by rev-erbs as well as the effect of heme on corepressor recruitment by the receptors.
Specific Aim 2 will determine the specificity of heme for rev-erb1/rev-erb2 using biochemical and cell-based approaches.
Specific Aim 3 will determine if heme plays an important role in rev-erb signaling during physiological processes. These studies are essential for our understanding how ligands may coordinate rev-erb regulated metabolism, and more generally, how metabolic pathways are regulated by the external environment such as nutrient status. Since nuclear hormone receptors characterized as ligand-regulated have been definitively shown to be effective targets for the development of pharmaceuticals, we predict that our proposed studies may provide the basis for novel therapeutics targeting rev-erb1 and rev-erb2 for treatment of metabolic disorders. Metabolic diseases associated with aberrant metabolism of carbohydrates and lipids are the cause of significant morbidity and mortality in older people in Western Society. We propose to characterize the role of a novel ligand, the porphyrin heme, in regulation of rev-erb1 and rev-erb2--two orphan nuclear hormone receptors that regulate the expression of key genes involved in lipid metabolism. Since nuclear hormone receptors characterized as ligand-regulated have been definitively shown to be effective targets for the development of pharmaceuticals, we predict that our proposed studies may provide the basis for novel therapeutics targeting rev-erb1 and rev-erb2 for treatment of metabolic disorders. (this is a sentence repeated from 7 lines up-I don't know whose mistake it is, but it should probably be deleted either way) ? ? ?
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