Regulation of REV-ERBalpha and REV-ERBbeta function of HEME

描述(申请人提供)：与碳水化合物和脂类代谢异常有关的代谢性疾病是西方社会老年人严重发病率和死亡率的原因。核受体超家族的几个成员调节与碳水化合物和脂肪代谢有关的关键基因的表达，以响应它们的配体，包括脂肪酸、胆汁酸、胆固醇代谢物、类固醇激素和亲脂性维生素衍生物。最近，调节脂质代谢的一对相关的孤儿核激素受体的配基REV-BER1和REV-ERB2被确定。长期的目标是确定这种配体，即卟啉血红素，在调节rev-erbs活性中的作用。我们的组织假说是：血红素是一个关键的配体，通过调节受体对辅阻遏物的亲和力，调节rev-erb1/2在控制脂质代谢和分化的基因中的作用。这一假说将在以下特定目标中进行检验：特定目标1将确定血红素对rev-erbs转录调控的影响以及血红素对受体重新招募辅阻遏子的影响。具体目标2将使用生化和基于细胞的方法确定血红素对rev-erb1/rev-erb2的特异性。具体目标3将确定血红素在生理过程中是否在rev-erb信号中发挥重要作用。这些研究对于我们了解配体如何协调rev-erb调节的代谢，以及更广泛地说，代谢途径如何受到外部环境(如营养状态)的调节是至关重要的。由于以配体调节为特征的核激素受体已被明确地证明是药物开发的有效靶点，我们预测我们提出的研究可能为以rev-erb1和rev-erB2为靶点的新药治疗代谢紊乱提供基础。与碳水化合物和脂类代谢异常相关的代谢性疾病是西方社会老年人发病率和死亡率的重要原因。我们建议表征一种新的配体，即卟啉血红素，在调节REV-BER1和REV-ERB2这两个孤儿核激素受体中的作用，这两个受体调节涉及脂代谢的关键基因的表达。由于以配体调节为特征的核激素受体已被明确地证明是药物开发的有效靶点，我们预测我们提出的研究可能为以rev-erb1和rev-erB2为靶点的新药治疗代谢紊乱提供基础。(这是一个从7行开始重复的句子--我不知道这是谁的错误，但无论哪种方式，它可能都应该被删除)

DESCRIPTION (provided by applicant): 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)