Circadian molecular regulation of the xenobiotic response

外源性反应的昼夜分子调节

• 批准号: 9016537
• 负责人: Katja A Lamia
• 金额: $ 41.87万
• 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/9016537
• 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 Transport; Drug toxicity; Enzymes; Genes; Genetic Transcription; Glucocorticoid Receptor; Glucose; Health; 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; Pharmacotherapy; Phosphorylation; Physiological; Physiological Processes; Physiology; Predisposition; Protein Isoforms; Public Health; Regulation; 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 therapeutic intervention; novel therapeutics; preference; pregnane X receptor; 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）：昼夜节律最近已被公认为是各种生理过程的调节剂，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几种药物，包括抗高血压汀类药物（例如Lipitor）和抗糖尿病药物二甲双胍（例如葡萄糖量）。但是，这些偏好的分子基础尚不清楚。该提议的基本假设是，可以通过改变对异种生物配体反应的核激素受体的功能来调节治疗药物的细胞运输和代谢。促进我们对这些受体和阻遏物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，定义异种生物转录网络的昼夜调节可以使现有和新型治疗化合物的最佳治疗时间预测。此外，对调节异种生物转录反应的核激素受体途径的昼夜调节可能会导致调节药物吸收，代谢和/或毒性的新策略。我们以前的研究将昼夜节律时钟成分加密斑块（CRY1和CRY2）确定为营养反应性转录调节剂，因为它们通过AMP激活的蛋白激酶（AMPK）易感性易感性，并且它们具有调节糖苷受体受体依赖性转录的能力。我们还通过驱动昼夜表达来确立肝脏昼夜节律的重要作用 包括AMPK在内的肝酶和转运蛋白。在这些研究的过程中，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，分子和生理方法来揭示昼夜节律时钟以及昼夜节律压抑剂Crier1和Cry2在核激素受体途径中的作用，并在核激素受体途径中cry1 cry1 cry1 cry1 and cry1 cry 2）：1）：1） 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 3）检查昼夜节律时钟，PXR和CAR在二甲双胍处理功效中的作用。