Circadian Repressors Cry1 and Cry2 Modulate Nuclear Hormone Receptor Function

描述（由申请人提供）：昼夜节律最近被认为是一系列生理和病理过程的调节剂，包括葡萄糖稳态、运动耐力、血压和肿瘤发生。候选人的长期目标是通过继续研究昼夜节律与细胞和有机体代谢之间的相互关系，开发新的代谢性疾病治疗方法。这一提议的一个基本假设是，代谢生理可以在转录水平上通过调节核激素受体（NR）功能的营养传感昼夜节律抑制因子来调节；推进我们对这些受体和抑制因子相互作用的功能理解可能会突出治疗代谢性疾病的新治疗策略。生物钟成分隐色素（Cry1和Cry2）是营养响应性转录调节因子，因为它们容易被amp激活的蛋白激酶（AMPK）磷酸化，从而导致蛋白酶体降解。初步研究表明，隐花色素与几种核激素受体相互作用并抑制它们，使它们成为一种新的营养反应性核受体辅抑制因子。核激素受体作为代谢生理几个方面的关键调节因子被广泛研究。生化、遗传、分子和生理方法将用于揭示Cry1和Cry2在控制葡萄糖稳态和运动生理学的核激素受体途径中的作用，具体目的如下：目的1，表征Cry1和Cry2在核激素受体依赖转录中的作用（分析Cry1和Cry2与哺乳动物核激素受体之间的物理和功能关联）；目的2，研究Cry1和Cry2在葡萄糖稳态中的作用（激素治疗前后Cry1缺陷小鼠葡萄糖调节的特征；肝脏中激素依赖基因调控的检测）；目的3，研究Cry1和Cry2在运动生理学中的作用（表征哭泣缺陷小鼠的肌肉生物学、生理学和运动耐力；检测药物治疗前后肌肉中的基因表达）。

DESCRIPTION (provided by applicant): Circadian rhythms have recently become recognized as modulators of a wide array of physiological and pathological processes, including glucose homeostasis, exercise endurance, blood pressure and tumorigenesis. The long-term goal of the candidate is to develop novel therapeutic approaches for metabolic disease by continuing to investigate the interrelationship between circadian rhythms and cellular and organismal metabolism. An underlying hypothesis of this proposal is that metabolic physiology can be modulated at the transcriptional level by nutrient-sensing circadian repressors regulating nuclear hormone receptor (NR) function; advancing our functional understanding of these receptor and repressor interactions may highlight new therapeutic strategies for treating metabolic disease. The circadian clock components cryptochromes (Cry1 and Cry2) are nutrient-responsive transcriptional regulators by virtue of their susceptibility to phosphorylation by AMP-activated protein kinase (AMPK), which causes their proteasomal degradation. Preliminary studies indicate that cryptochromes interact with and repress several nuclear hormone receptors, making them novel nutrient-responsive nuclear receptor corepressors. Nuclear hormone receptors are widely studied as critical regulators of several aspects of metabolic physiology. Biochemical, genetic, molecular and physiological approaches will be used to uncover the roles of Cry1 and Cry2 in nuclear hormone receptor pathways governing the control of glucose homeostasis and exercise physiology, in the following specific aims: Aim I, characterize the roles of Cry1 and Cry2 in nuclear hormone receptor-dependent transcription (analysis of the physical and functional associations between Cry1 and Cry2 and mammalian nuclear hormone receptors); Aim 2, examine the roles of Cry1 and Cry2 in glucose homeostasis (characterization of glucose regulation in Cry-deficient mice before and after hormone treatment; examination of hormone-dependent gene regulation in livers); Aim 3, examine the roles of Cry1 and Cry2 in exercise physiology (characterize muscle biology, physiology and exercise endurance in Cry-deficient mice; examine gene expression in muscles before and after pharmacological treatments). PUBLIC HEALTH RELEVANCE: Diabetes and the metabolic syndrome are growing public health concerns in the United States. Nuclear hormone receptors govern a wide array of metabolic physiological processes, the disruption of which contributes to metabolic disorders. This project involves the study of a novel regulator for nuclear hormone receptor function and will contribute to the knowledge base needed for the development of therapeutic strategies to treat metabolic disease.