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) ? ? ?
| Sitaula, Sadichha; Zhang, Jinsong; Ruiz, Fernanda et al. (2017) Rev-erb regulation of cholesterologenesis. Biochem Pharmacol 131:68-77 |
| Solt, Laura A; Banerjee, Subhashis; Campbell, Sean et al. (2015) ROR inverse agonist suppresses insulitis and prevents hyperglycemia in a mouse model of type 1 diabetes. Endocrinology 156:869-81 |
| Matta-Camacho, Edna; Banerjee, Subhashis; Hughes, Travis S et al. (2014) Structure of REV-ERB? ligand-binding domain bound to a porphyrin antagonist. J Biol Chem 289:20054-66 |
| Kojetin, Douglas J; Burris, Thomas P (2013) Small molecule modulation of nuclear receptor conformational dynamics: implications for function and drug discovery. Mol Pharmacol 83:1-8 |
| Woldt, Estelle; Sebti, Yasmine; Solt, Laura A et al. (2013) Rev-erb-? modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy. Nat Med 19:1039-46 |
| Kumar, Naresh; Lyda, Brent; Chang, Mi Ra et al. (2012) Identification of SR2211: a potent synthetic ROR?-selective modulator. ACS Chem Biol 7:672-7 |
| Noel, Romain; Song, Xinyi; Shin, Youseung et al. (2012) Synthesis and SAR of tetrahydroisoquinolines as Rev-erbýý agonists. Bioorg Med Chem Lett 22:3739-42 |
| Crumbley, Christine; Wang, Yongjun; Banerjee, Subhashis et al. (2012) Regulation of expression of citrate synthase by the retinoic acid receptor-related orphan receptor * (ROR*). PLoS One 7:e33804 |
| Solt, Laura A; Kamenecka, Theodore M; Burris, Thomas P (2012) LXR-mediated inhibition of CD4+ T helper cells. PLoS One 7:e46615 |
| Shin, Youseung; Noel, Romain; Banerjee, Subhashis et al. (2012) Small molecule tertiary amines as agonists of the nuclear hormone receptor Rev-erbýý. Bioorg Med Chem Lett 22:4413-7 |
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