Circadian Repressors Cry1 and Cry2 Modulate Nuclear Hormone Receptor Function

描述(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器，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机体代谢之间的相互关系来开发代谢性疾病的新治疗方法。这一建议的一个基本假设是，代谢生理可以通过调节核激素受体(NR)功能的营养感知昼夜节律抑制因子在转录水平上进行调节；提高我们对这些受体和抑制因子相互作用的功能理解可能会为治疗代谢性疾病提供新的治疗策略。生物钟成分隐花素(Cry1和Cry2)是营养响应的转录调节因子，因为它们容易被AMP激活的蛋白激酶(AMPK)磷酸化，从而导致它们的蛋白酶体降解。初步研究表明，隐花色素与多种核激素受体相互作用并抑制它们，使它们成为新的营养响应核受体辅阻遏物。核激素受体被广泛研究为代谢生理学的几个方面的关键调节因子。将通过生物化学、遗传学、分子和生理学的方法揭示Cry1和Cry2在核激素受体调控葡萄糖稳态和运动生理学中的作用，具体目的如下：目的1，研究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的物理和功能联系)；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和Cry2缺陷小鼠的葡萄糖调节特征；肝脏激素依赖性基因调控)；目的：研究Cry1和Cry2在运动生理学中的作用(研究Cry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的基因表达)。 与公共健康相关：在美国，糖尿病和代谢综合征日益引起公众的关注。核激素受体控制着广泛的代谢生理过程，这些过程的破坏会导致代谢紊乱。该项目涉及一种新的核激素受体功能调节剂的研究，并将有助于开发治疗代谢性疾病的治疗策略所需的知识库。

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.