CIRCADIAN PATTERN OF REST-ACTIVITY RHYTHMS AND BLOOD PRESSURE AND THE UNDERLYING

项目摘要： 近一半的美国成年人患有HTN，这是心血管疾病（CVD）的最强风险因素之一 也是心血管疾病死亡的主要原因。血压（BP）显示昼夜节律，并且 昼夜血压变化与CVD发病率和死亡率有关。新出现的证据表明， 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，令人担忧的HTN患病率已经从白天为主转变为白天为主。 延迟的生活方式，即晚上进食和活动，睡眠受到限制。干预研究表明 昼夜节律紊乱对血压的影响在大小上类似，但方向相反， 停止高血压的饮食方法（DASH）饮食和某些抗高血压药物。但这些 研究并不能反映现实生活中的习惯行为模式，也不能捕捉长期的健康影响 温和的昼夜节律失调，这是非常普遍的人口，并尚未阐明潜在的 机制等这个K99/R 00奖的研究目标是评估昼夜休息活动的关联 昼夜节律（CRAR），自由生活环境中的昼夜节律性指标，伴有HTN风险和昼夜BP 变异和调查表观遗传途径作为一个潜在的机制。我在寻找通往 独立奖，以获得额外的培训需要实现我的长期职业目标：成为一个 跨学科的独立科学家，专门研究行为风险因素，昼夜节律 节律和表观遗传学与心血管风险的关系。该项目的培训部分将提供 专长：1）昼夜节律的概念和方法，2）设计和分析人类表观遗传学（DNA 甲基化）研究，3）先进的统计方法，以及4）动态血压的收集和解释 监测（ABPM）数据。这将通过正式的课程作业，指导阅读和教学 指导、研究学徒、参加学术研讨会和会议以及指导职业生涯 开发活动，包括编写赠款。该项目的研究部分将利用目标 来自多种族动脉粥样硬化研究（梅萨）的睡眠和活动数据，并使用非参数 方法估计昼夜节律的休息活动模式。在目标1中，我们将研究 CRAR与HTN患病率和发生率，并阐明潜在的性别和种族/民族差异。在目标2中， 我们将研究CRAR，表观遗传年龄（一种基于DNA的生物衰老指标）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了 与HTN的CRAR。为扩展这项工作，为目标3的研究报告01作好准备，我们会进行一项试验研究， 检查CRAR、表观遗传年龄和24小时ABPM测量之间的关联。培训和 研究活动将产生科学报告、出版物和初步数据，并为我做好准备， 在R 00阶段成功竞争R 01资金。

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.