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

• 批准号: 8055969
• 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
• 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/8055969
• 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

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.

性状（由申请人提供）：醛固酮是调节钠（Na）稳态的主要盐皮质激素，其作用有助于维持血压和心脏功能。异常的醛固酮信号可以导致高血压，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，心血管疾病是美国的主要死因。大多数已知的高血压的单基因原因是由于醛固酮作用的下游靶点的缺陷。醛固酮的作用机制主要是转录的，大多数已知的基因靶点集中在肾上皮钠通道（ENaC）上。最近的数据表明，醛固酮靶点周期1（一种昼夜节律基因）在介导ENaC α亚基（（ENaC），肾脏Na通道的限速亚基）的醛固酮依赖性和非依赖性调节中发挥作用。许多生理过程表现出昼夜节律模式，包括睡眠-觉醒周期、心跳、激素分泌、肾血流量和血压。然而，生物钟在调节这些过程中的作用在分子水平上还不清楚。这些研究的长期目标是描述生物钟在高血压和心血管疾病中的作用。本申请的目标是定义Per 1在（ENaC.为此，本提案的目的是（1）表征Per 1介导的ENaC基因的转录调节，（2）确定Per 1在ENaC活性调节中的作用，和（3）评估Per 1在体内ENaC调节中的作用。ENaC和生物钟之间直接的分子和生理联系的证据可能对理解肾脏Na处理和可能的病理生理条件下的血压控制具有深远的意义。候选人将使用本提案中描述的工作作为基础，开发一个独立的研究路线，研究肾脏中的昼夜节律和醛固酮介导的Na转运控制。因此，设计了一个全面的培训方案，以使申请人成为独立调查员。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学培训以及肾脏生理学和负责任的研究行为的额外培训。查尔斯·温戈博士，一位备受推崇的肾病学家和肾脏离子转运专家，将担任候选人的导师。已经成立了一个咨询委员会，以帮助候选人在科学和职业发展。Charles Wingo、Mark Segal、Julie约翰逊、Barbara Battelle和道格拉斯伊顿博士是肾脏学、生理学、药理学和神经科学领域的专家。佛罗里达大学的优秀环境，丰富的临床和基础科学，加上科学的计划和全面的培训计划，将为候选人提供实现她成为肾生理学领域独立研究者的目标的最佳机会。 公共卫生相关性：许多重要的生理过程，如血压和肾功能显示昼夜节律。这些过程和生物钟之间的联系尚不清楚。通过描述生物钟蛋白Per 1在肾钠转运调节中的作用，我们可以开始了解生物钟、肾功能和血压之间的联系。