Circadian Pattern of Rest-Activity Rhythms and Blood Pressure and the Underlying Epigenetic Mechanisms

休息活动节律和血压的昼夜节律模式及其潜在的表观遗传机制

• 批准号: 9806535
• 负责人: Nour Makarem
• 金额: $ 12.94万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9806535
• 关键词: Acceleration; Address; Adult; Affect; Age; Aging; Ambulatory Blood Pressure Monitoring; Ancillary Study; Antihypertensive Agents; Award; Behavior; Behavior Therapy; Behavioral; Biological; Biological Aging; Biological Clocks; Biological Markers; Blood Pressure; Cardiovascular Diseases; Cardiovascular system; Circadian Dysregulation; Circadian Rhythms; Circadian desynchrony; Collection; Cues; DASH diet; DNA Methylation; Data; Disease; Disease susceptibility; Eating; Epigenetic Process; Etiology; Event; Frequencies; Funding; Goals; Grant; Guidelines; Health; Human; Hypertension; Incidence; Individual; Instruction; Intervention Studies; Lead; Life; Life Style; Link; Measures; Mediating; Mentors; Methods; Modeling; Modernization; Monitor; Morbidity - disease rate; Multi-Ethnic Study of Atherosclerosis; National Heart, Lung, and Blood Institute; Pathway interactions; Pattern; Periodicity; Pharmaceutical Preparations; Phase; Physiological; Pilot Projects; Population; Predisposition; Preparation; Prevalence; Prevention; Prevention Guidelines; Publications; Reading; Research; Research Activity; Research Priority; Rest; Risk; Risk Factors; Scientist; Sex Differences; Sleep; Societies; Statistical Methods; Training; Training Activity; Variant; Vision; Woman; Work; Writing; age related; apprenticeship; awake; base; cardiovascular disorder risk; cardiovascular risk factor; career; career development; circadian; design; epidemiology study; epigenome; ethnic difference; ethnic disparity; ethnic minority population; hypertension prevention; improved; insight; interdisciplinary approach; methylation pattern; mortality; novel; prognostic significance; prospective; racial and ethnic; sex; statistics; symposium

Project Summary: Nearly half of US adults present with HTN, one of the strongest risk factors for cardiovascular disease (CVD) and a leading cause of CVD mortality. Blood pressure (BP) displays a circadian rhythm, and abnormalities in diurnal BP variation are linked to CVD morbidity and mortality. Emerging evidence suggests that the circadian rhythmicity of behavioral factors within the 24-h day can alter BP levels and their natural variation patterns. Interestingly, the alarming HTN prevalence rates have paralleled the shift from a predominantly daytime to a delayed lifestyle, in which eating and activity occur at night and sleep is restricted. Intervention studies suggest that the effect of circadian disruption on BP is similar in magnitude but opposite in direction to that of the Dietary Approaches to Stop Hypertension (DASH) diet and certain anti-hypertensive drugs. However, these studies do not reflect habitual patterns of behavior in a real-life setting, do not capture long-term health effects of milder circadian misalignment that is highly prevalent in the population, and have yet to elucidate underlying mechanisms. The research goal of this K99/R00 award is to evaluate the associations of circadian rest-activity rhythms (CRAR), a measure of circadian rhythmicity in the free-living setting, with HTN risk and diurnal BP variation and investigate epigenetic pathways as an underlying mechanism. I am seeking the Pathway to Independence Award to gain the additional training needed to accomplish my long-term career goal: to be an interdisciplinary independent scientist who specializes in the intersection of behavioral risk factors, circadian rhythms, and epigenetics in relation cardiovascular risk. The training component of this project will provide expertise in: 1) circadian concepts and methods, 2) design and analysis of human epigenetics (DNA methylation) studies, 3) advanced statistical methods, and 4) collection and interpretation of ambulatory BP monitoring (ABPM) data. This will be accomplished through formal coursework, directed readings and didactic instruction, research apprenticeships, attendance to scholarly seminars and conferences, and mentored career development activities including grant writing. The research component of this project will leverage objective sleep and activity data from the Multi-Ethnic Study of Atherosclerosis (MESA) and use non-parametric methods to estimate circadian rhythm of rest-activity patterns. In Aim 1, we will investigate associations of CRAR with HTN prevalence and incidence and elucidate potential sex and racial/ethnic differences. In Aim 2, we will examine the relations between CRAR, epigenetic age (a measure of biological aging based on DNA methylation patterns), and BP and determine whether epigenetic age acceleration mediates associations of CRAR with HTN. To extend this work in preparation for an R01, for Aim 3, we will conduct a pilot study to examine the associations between CRAR, epigenetic age, and 24-h ABPM measures. The training and research activities will result in scientific presentations, publications, and preliminary data and prepare me to successfully compete for R01 funding during the R00 phase.

项目概要： 近一半的美国成年人患有高血压，这是心血管疾病 (CVD) 的最强危险因素之一 也是 CVD 死亡的主要原因。血压 (BP) 显示昼夜节律和异常 每日血压变化与心血管疾病发病率和死亡率有关。新出现的证据表明，昼夜节律 一天 24 小时内行为因素的节律性可以改变血压水平及其自然变化模式。 有趣的是，令人震惊的高血压患病率与从以白天为主向以白天为主的转变同时发生。 延迟的生活方式，即饮食和活动发生在夜间，睡眠受到限制。干预研究表明 昼夜节律紊乱对血压的影响与昼夜节律紊乱的影响程度相似，但方向相反 控制高血压的饮食方法 (DASH) 饮食和某些抗高血压药物。然而，这些 研究不反映现实生活中的习惯行为模式，也不捕捉长期的健康影响 较轻微的昼夜节律失调在人群中非常普遍，但尚未阐明潜在的原因 机制。该 K99/R00 奖项的研究目标是评估昼夜节律休息活动的关联 节律 (CRAR)，衡量自由生活环境中昼夜节律的指标，包括高血压风险和昼夜血压 变异并研究表观遗传途径作为潜在机制。我正在寻找通往 独立奖以获得实现我的长期职业目标所需的额外培训：成为一名 跨学科独立科学家，专门研究行为风险因素、昼夜节律的交叉点 节律和表观遗传学与心血管风险相关。该项目的培训部分将提供 专业知识：1) 昼夜节律概念和方法，2) 人类表观遗传学（DNA）的设计和分析 甲基化）研究，3）先进的统计方法，4）动态血压的收集和解释 监测（ABPM）数据。这将通过正式课程、定向阅读和教学来完成 指导、研究学徒、参加学术研讨会和会议以及职业指导 开发活动，包括撰写赠款。该项目的研究部分将利用目标 来自动脉粥样硬化多种族研究 (MESA) 的睡眠和活动数据，并使用非参数 估计休息活动模式的昼夜节律的方法。在目标 1 中，我们将调查以下关联： CRAR 揭示了 HTN 患病率和发病率，并阐明了潜在的性别和种族/民族差异。在目标 2 中， 我们将研究 CRAR、表观遗传年龄（基于 DNA 的生物衰老测量方法）之间的关系 甲基化模式）和 BP 并确定表观遗传年龄加速是否介导以下关联： CRAR 与 HTN。为了扩展这项工作，为目标 3 的 R01 做准备，我们将进行一项试点研究 检查 CRAR、表观遗传年龄和 24 小时 ABPM 测量值之间的关联。培训和 研究活动将产生科学演示、出版物和初步数据，并使我做好准备 在R00阶段成功竞争R01资金。