A Functional Role for the Circadian Clock Protein Per1 in the Regulation of ??ENa

生物钟蛋白 Per1 在 ENa 调节中的功能作用

基本信息

批准号：
8637987
负责人：
Michelle L Gumz
金额：
$ 12.56万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-05 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8637987
关键词：
Adult Advisory Committees Affect Affinity Chromatography Aldosterone American Attenuated Basic Science Binding Biological Assay Blood Blood Pressure Bolus Infusion Cardiac Cardiovascular Diseases Cause of Death Cells Circadian Rhythms Clinical Sciences Clock protein DNA Data Defect Diet Dominant-Negative Mutation Duct (organ) structure Elements Environment Epithelial Exhibits Family Florida Gene Expression Gene Targeting Genes Goals Health Heart Heart failure Helix-Turn-Helix Motifs Homeostasis Hormones Hypertension Ion Transport Journals Kidney Knock-out Knockout Mice Lead Link Luciferases Maintenance Measures Mediating Medical Mentors Messenger RNA Mineralocorticoid Receptor Mineralocorticoids Molecular Monitor Mus Mutagenesis Nephrology Neurosciences Pathway interactions Patients Pattern Pharmacology Physiological Physiological Processes Physiology Process Proteins Regulation Renal Blood Flow Renal function Reporter Research Research Personnel Response Elements Risk Factors Role Signal Transduction Sleep Wake Cycle Sodium Sodium Channel Syndrome Testing Training Training Programs Transcriptional Regulation United States Universities Urine Western Blotting Wild Type Mouse Work base blood pressure regulation career career development chromatin immunoprecipitation chromatin modification circadian pacemaker design epithelial Na+ channel feeding in vivo knockout animal mRNA Expression member mortality novel promoter response responsible research conduct sudden cardiac death transcription factor

项目摘要

DESCRIPTION (provided by applicant): Aldosterone is the major mineralocorticoid hormone that regulates sodium (Na) homeostasis and its action contributes to the maintenance of blood pressure and cardiac function. Abnormal aldosterone signaling can lead to hypertension, a syndrome that affects at least 25% of American adults. Hypertension is a primary risk factor for cardiovascular disease, the leading cause of death in the United States. Most known monogenetic causes of hypertension are due to a defect in the downstream targets of aldosterone action. The mechanism of aldosterone action is largely transcriptional with most known gene targets converging on the renal epithelial sodium channel (ENaC). Recent data suggest a role for the aldosterone target Period 1, a circadian rhythm gene, in mediating the aldosterone-dependent and independent regulation of the alpha subunit of ENaC ((ENaC), the rate limiting subunit for the Na channel in the kidney. Many physiological processes exhibit a circadian pattern, including the sleep-wake cycle, heart beat, hormone secretion, renal blood flow, and blood pressure. However, the role of the circadian clock in the regulation of these processes is not understood at a molecular level. The long term goal of these studies is to characterize the role of the circadian clock in hypertension and cardiovascular disease. The goal of the present application is to define a functional role for Per1 in the regulation of (ENaC. To this end, the aims of this proposal are to (1) characterize the Per1-mediated transcriptional regulation of the (ENaC gene, (2) define the role of Per1 in the regulation of ENaC activity, and (3) evaluate the role of Per1 in the regulation of (ENaC in vivo. Evidence of a direct molecular and physiological link between ENaC and the circadian clock is likely to have profound implications for understanding renal Na handling and possibly blood pressure control in pathophysiological conditions. The candidate will use the work described in this proposal as the basis for developing an independent line of research into circadian and aldosterone-mediated control of Na transport in the kidney. Thus, a comprehensive training program has been designed to move the applicant to a career as an independent investigator. Didactic coursework, seminars and journal clubs will provide the candidate with new and formal training in physiology as well as additional training in renal physiology and the responsible conduct of research. Dr. Charles Wingo, a highly regarded nephrologist and expert in renal ion transport, will serve as the candidate's mentor. An Advisory Committee has been assembled to aid the candidate in scientific and career development. Drs. Charles Wingo, Mark Segal, Julie Johnson, Barbara Battelle and Douglas Eaton are experts in the fields of nephrology, physiology, pharmacology, and neuroscience. The outstanding environment of the University of Florida, rich in clinical and basic sciences, together with the scientific plan and comprehensive training program, will offer the candidate the best opportunity for achieving her goal of becoming an independent investigator in the field of renal physiology. PUBLIC HEALTH RELEVANCE: Many important physiological processes such as blood pressure and kidney function display a circadian rhythm. The link between these processes and the circadian clock is not understood. By characterizing the role of the circadian clock protein Per1 in the regulation of renal sodium transport, we can begin to understand the connection between the circadian clock, kidney function and blood pressure.

描述（由申请人提供）：醛固酮是调节钠（NA）稳态的主要矿物皮质激素，其作用有助于维持血压和心脏功能。异常的醛固酮信号传导可导致高血压，这是一种影响至少25％的美国成年人的综合征。高血压是心血管疾病的主要危险因素，这是美国的主要死亡原因。高血压的最著名的单基因原因是由于醛固酮作用的下游靶标的缺陷所致。醛固酮作用的机制在很大程度上是转录的，其中大多数已知的基因靶标在肾上皮钠通道（ENAC）上融合。 Recent data suggest a role for the aldosterone target Period 1, a circadian rhythm gene, in mediating the aldosterone-dependent and independent regulation of the alpha subunit of ENaC ((ENaC), the rate limiting subunit for the Na channel in the kidney. Many physiological processes exhibit a circadian pattern, including the sleep-wake cycle, heart beat, hormone secretion, renal blood flow, and blood pressure. However, the role在分子水平上，这些过程中的调节中的昼夜节律的长期目标是表征昼夜节律时钟在高血压和心血管疾病中的作用。基因，（2）定义了PER1在ENAC活性调节中的作用，（3）评估PER1在调节（ENAC INAC体内）中的作用。 ENAC与昼夜节律时钟之间直接分子和生理联系的证据可能对理解肾脏NA处理以及在病理生理状况下可能控制血压的影响有深远的影响。候选人将使用本提案中描述的工作作为将独立研究的基础开发到肾脏中NA运输的昼夜节律和醛固酮介导的控制中。因此，已经设计了一项全面的培训计划，以使申请人成为独立调查员的职业。教学课程，研讨会和期刊俱乐部将为候选人提供新的和正式的生理培训，以及肾脏生理学和负责任的研究的其他培训。 Charles Wingo博士是一位备受推崇的肾脏医生，肾脏离子运输专家，将担任候选人的导师。咨询委员会已组建，以帮助候选人进行科学和职业发展。博士。查尔斯·温戈（Charles Wingo），马克·塞加尔（Mark Segal），朱莉·约翰逊（Julie Johnson），芭芭拉·巴特尔（Barbara Battelle）和道格拉斯·伊顿（Douglas Eaton）是肾脏学，生理学，药理学和神经科学领域的专家。佛罗里达大学的杰出环境，丰富的临床和基础科学以及科学计划和综合培训计划，将为候选人提供最佳机会，以实现她成为肾脏生理学领域的独立研究者的目标。公共卫生相关性：许多重要的生理过程，例如血压和肾脏功能表现出昼夜节律。这些过程与昼夜节律之间的联系尚不清楚。通过表征昼夜节律蛋白质PER1在肾脏钠转运调节中的作用，我们可以开始了解昼夜节律时钟，肾脏功能和血压之间的联系。