Transcriptional Regulation of KCNH2

KCNH2 的转录调控

基本信息

批准号：
9889985
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-08 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9889985
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 Phase Phenotype Physiological Pluripotent Stem Cells 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 insight mRNA Stability molecular clock mouse model premature promoter shift work suprachiasmatic nucleus transcription factor

项目摘要

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.

概括昼夜节律有助于使心血管系统的最佳功能与每日的变化相匹配环境。正常的心血管节律为人们提供了生理优势。很遗憾，正常的昼夜节律信号还可以揭示心脏病发作、中风、以及患有潜在心血管疾病的患者突然死亡。现在的新数据表明，异常或不健康的日常节律会对正常的生活节奏产生负面影响。健康也。例如，轮班工作会反复导致内源性昼夜节律发生变化，这是一种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，有助于将内源节律带入环境。 SCN节律通过光与环境同步，它的信号传导有助于协调全身细胞的分子节律。有什么新内容该应用程序是我们确定光周期的重复变化将如何影响分子昼夜节律信号传导心脏。大多数细胞具有分子时钟信号传导机制，其周期约为 24 小时。我们发现心脏细胞（心肌细胞）分子时钟机制的遗传破坏主要导致通过扰乱离子通道功能的调节而导致心脏电生理学的异常变化。该应用的目标是确定光周期的重复变化如何影响分子钟小鼠心脏中的信号传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 2. 确定光的重复变化如何影响心脏和离子中的分子钟信号传导渠道监管。该项目在时间生物学和心脏电生理学之间创造了新的知识。