Circadian molecular regulation of the xenobiotic response

外源性反应的昼夜分子调节

• 批准号: 8629737
• 负责人: Katja A Lamia
• 金额: $ 41.22万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629737
• 关键词: 5' -AMP-activated protein kinase; Agonist; Antidiabetic Drugs; Antihypertensive Agents; Automobile Driving; Behavior; Biochemical; Biochemical Genetics; Biological Assay; Blood Pressure; CYP3A4 gene; Cells; Charge; Chromatin; Circadian Rhythms; Dependence; Development; Diabetes Mellitus; Disease; Drug Prescriptions; Drug Transport; Drug toxicity; Enzymes; Genes; Genetic Transcription; Glucocorticoid Receptor; Glucose; Hepatic; Hepatocyte; Human; Lead; Ligands; Liver; Marketing; Measures; Mediating; Metabolic Diseases; Metabolic syndrome; Metabolism; Metformin; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Hormone Receptors; Nutrient; POU2F1 gene; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Physiological; Physiological Processes; Physiology; Predisposition; Protein Isoforms; Public Health; Regulation; Relative (related person); Repression; Role; Specificity; Tertiary Protein Structure; Therapeutic; Time; Toxic effect; Transcript; Transcriptional Regulation; Treatment Efficacy; United States; Xenobiotic Metabolism; Xenobiotics; absorption; atorvastatin; base; blood glucose regulation; circadian pacemaker; cryptochrome; drug metabolism; glucophage; in vivo; insight; knowledge base; novel; novel therapeutics; preference; pregnane X receptor; public health relevance; receptor; response; small molecule; tool; uptake

DESCRIPTION (provided by applicant): Circadian clocks have recently become recognized as modulators of a wide array of physiological processes, including glucose homeostasis, blood pressure modulation, and drug metabolism and toxicity. Several drugs, including the anti-hypertensive statins (e.g. Lipitor) and the anti-diabetic drug metformin (e.g. Glucophage), are recommended to be taken at specific times of day. However, the molecular basis for these preferences is not well understood. The underlying hypothesis of this proposal is that the cellular transport and metabolism of therapeutic drugs can be modulated at the transcriptional level by circadian repressors altering the function of nuclear hormone receptors that respond to xenobiotic ligands. Advancing our functional understanding of these receptor and repressor interactions may highlight new therapeutic strategies for treating disease. For example, defining the diurnal regulation of the xenobiotic transcriptional network could enable the prediction of optimal treatment times for existing and novel therapeutic compounds. In addition, a deeper understanding of the diurnal regulation of nuclear hormone receptor pathways that modulate the xenobiotic transcriptional response may lead to new strategies for modulating drug absorption, metabolism and/or toxicities. Our previous studies identified the circadian clock component cryptochromes (Cry1 and Cry2) as nutrient- responsive transcriptional regulators by virtue of their susceptibility to phosphorylation by AMP-activated protein kinase (AMPK) and their ability to modulate glucocorticoid receptor dependent transcription. We have also established an important role for the liver circadian clock in glucose homeostasis, via driving diurnal expression of hepatic enzymes and transporters, including AMPK. In the course of those studies, we have generated unique tools and expertise that enables us to use biochemical, genetic, molecular and physiological approaches to uncover the roles of circadian clocks and of the circadian repressors Cry1 and Cry2 specifically in nuclear hormone receptor pathways governing the control of drug transport and metabolism, in the following specific aims: 1) Characterize the interactions of Cry1 and Cry2 with the xenobiotic receptors PXR and CAR (define the species and isoform specificity and ligand dependence of cryptochrome-xenobiotic receptor interactions; identify domains and sequences required for interaction), 2) Define the role of Cry1 and Cry2 in the regulation of PXR/CAR-mediated xenobiotic metabolism (identify specific transcriptional targets of PXR and CAR that are regulated by cryptochromes, measure changes in drug transport and metabolizing activities upon cryptochrome depletion), 3) Examine the roles of circadian clocks, PXR and CAR in the efficacy of metformin treatment.

描述（由申请人提供）：生物钟最近被认为是多种生理过程的调节器，包括葡萄糖稳态、血压调节以及药物代谢和毒性。建议在一天中的特定时间服用多种药物，包括抗高血压他汀类药物（例如立普妥）和抗糖尿病药物二甲双胍（例如格华止）。然而，这些偏好的分子基础尚不清楚。该提议的基本假设是，治疗药物的细胞转运和代谢可以通过昼夜节律抑制因子在转录水平上进行调节，从而改变对外源配体做出反应的核激素受体的功能。增进我们对这些受体和阻遏蛋白相互作用的功能理解可能会突出治疗疾病的新治疗策略。例如，定义外源性转录网络的昼夜调节可以预测现有和新型治疗化合物的最佳治疗时间。此外，对调节外源转录反应的核激素受体途径的昼夜调节的更深入了解可能会导致调节药物吸收、代谢和/或毒性的新策略。我们之前的研究将生物钟成分隐花色素（Cry1 和 Cry2）确定为营养响应性转录调节因子，因为它们对 AMP 激活蛋白激酶 (AMPK) 磷酸化的敏感性以及调节糖皮质激素受体依赖性转录的能力。我们还通过驱动昼夜表达确定了肝脏生物钟在葡萄糖稳态中的重要作用 肝酶和转运蛋白，包括 AMPK。在这些研究过程中，我们产生了独特的工具和专业知识，使我们能够使用生化、遗传、分子和生理学方法来揭示生物钟和昼夜节律抑制因子 Cry1 和 Cry2 的作用，特别是在控制药物转运和代谢的核激素受体途径中，具体目标如下：1) 表征 Cry1 和 Cry2 与外源物质的相互作用 受体 PXR 和 CAR（定义隐花色素-异生物质受体相互作用的种类和亚型特异性以及配体依赖性；识别相互作用所需的结构域和序列），2) 定义 Cry1 和 Cry2 在 PXR/CAR 介导的外源代谢调节中的作用（识别受隐花色素调节的 PXR 和 CAR 的特定转录靶标，测量药物转运的变化 和隐花色素耗尽时的代谢活动），3）检查生物钟、PXR 和 CAR 在二甲双胍治疗功效中的作用。