Transcriptional Regulation of KCNH2

KCNH2 的转录调控

• 批准号: 10366053
• 负责人: Brian P Delisle
• 金额: $ 57.1万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-08 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10366053
• 关键词: ARNTL gene; Action Potentials; Adverse event; Arrhythmia; Biological Assay; Bioluminescence; Brain; Cardiac; Cardiac Electrophysiologic Techniques; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cells; Cessation of life; Chemistry; Chronic; Chronobiology; Circadian Rhythms; Cues; Data; Electrophoretic Mobility Shift Assay; Elements; Environment; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Half-Life; Health; Heart; Hour; Human; Hypothalamic structure; Incidence; Ion Channel; Knowledge; Kv channel-interacting protein 2; Label; Length; Light; Long QT Syndrome; Mammals; Measures; Messenger RNA; Molecular; Molecular Target; Mus; Myocardial Infarction; Patients; Pattern; Periodicity; Persons; Phase; Phenotype; Physiological; Potassium Channel; Premature Mortality; Proteins; RNA; Regulation; Reporter Genes; Role; Signal Transduction; Stroke; Sudden Death; Telemetry; Testing; Time; Tissues; Transcript; Transcriptional Regulation; Transgenic Mice; Uridine; cardiovascular risk factor; chromatin immunoprecipitation; circadian; circadian pacemaker; heart cell; in vivo; induced pluripotent stem cell; insight; mRNA Stability; molecular clock; mouse model; premature; promoter; shift work; suprachiasmatic nucleus; transcription factor

Summary Circadian rhythms help to match the optimal function of the cardiovascular system to the daily changes in the environment. Normal cardiovascular rhythms provide a physiological advantage to people. Unfortunately, normal circadian signaling can also unmask a time-of-day pattern in adverse events like heart attack, stroke, and sudden death in patients with underlying cardiovascular disease. Emerging data now show that abnormal or unhealthy daily rhythms can create a negative impact on normal health too. For example shiftwork, which repeatedly causes shifts in endogenous circadian rhythms, is an independent risk factor for cardiovascular disease. In mammals the suprachiasmatic nucleus (SCN) in the brain is the primary circadian pacemaker that helps to entrain endogenous rhythms to the environment. SCN rhythms are synchronized to the environment via light, and its signaling helps to coordinate the molecular rhythms in cells throughout the body. What is new about this application is we determine how repeated changes in light cycle will impact molecular circadian signaling in the heart. Most cells have a molecular clock signaling mechanism that cycles with a periodicity of ~24 hours. We found genetic disruptions in the molecular clock mechanism of heart cells (cardiomyocytes) primarily causes abnormal changes in cardiac electrophysiology by disrupting the regulation of ion channel function. The goal of this application is to determine how repeated shifts in the light cycle impact molecular clock signaling in the mouse heart and its regulation on ion channel function. Aim 1. To identify new mechanisms with which the cardiac molecular clock regulates different ion channels. Aim 2. To determine how repeated changes in light impact molecular clock signaling in the heart and ion channel regulation. This project creates new knowledge at the interface between chronobiology and cardiac electrophysiology.

总结 昼夜节律有助于使心血管系统的最佳功能与心脏的每日变化相匹配。 环境正常的心血管节律为人们提供了生理优势。不幸的是， 正常的昼夜节律信号也可以揭示不良事件如心脏病发作，中风， 和潜在心血管疾病患者的猝死。 新出现的数据表明，不正常或不健康的日常节奏会对正常的生活产生负面影响。 健康也是。例如，轮班工作反复引起内源性昼夜节律的变化， 心血管疾病的独立危险因素。 在哺乳动物中，大脑中的视交叉上核（SCN）是主要的昼夜节律起搏器，有助于 将内源性节律带入环境。SCN节律通过光与环境同步， 它的信号有助于协调全身细胞的分子节奏。关于我们 这个应用是我们确定光周期的重复变化如何影响分子昼夜信号， 心脏 大多数细胞都有一个分子时钟信号机制，周期约为24小时。我们发现 心脏细胞（心肌细胞）分子钟机制的遗传破坏主要导致 通过破坏离子通道功能的调节而引起的心脏电生理学的异常变化。 这个应用程序的目标是确定光周期中的重复变化如何影响分子钟 信号转导及其对离子通道功能的调节。 目标1.确定心脏分子钟调节不同离子通道的新机制。 目标二。为了确定光的重复变化如何影响心脏和离子中的分子钟信号， 渠道监管 这个项目在时间生物学和心脏电生理学之间的界面上创造了新的知识。