Endogenous circadian mechanisms underlying cardiovascular risk

项目总结/摘要 内源性生物钟存在于所有细胞和组织中，包括自主神经系统、心脏和神经系统。 脉管系统由此产生的节律使心血管（CV）系统为最佳功能做好准备，以匹配 日常预期的行为和环境周期，如改变姿势和增加活动后， 早上醒来。然而，早晨也是最容易发生心血管不良事件的时间， 包括心肌梗塞、中风和心脏性猝死。谢伊博士率先使用密集的， 多日的实验室实验，并发现了大量的内源性昼夜节律的CV 健康人的系统。Shea博士还发现，心血管对压力源的反应存在昼夜节律 (i.e.,在一天的不同时间对相同的应激源有不同的CV反应）。谢伊博士的工作 CV系统中的昼夜节律作为一把“双刃剑”的概念：正常的放大 早晨的反应有助于健康个体从睡眠到活动的过渡，但这种夸张的反应可能会导致睡眠过度。 在具有潜在CV风险因素的个体中， 事件Shea博士将领导一个由杰出研究人员组成的多学科团队， 昼夜节律系统如何与行为相关的CV反应相互作用，以产生可预测的每日变化 心血管风险特征。为了与健康对照进行比较，将在具有增加的 潜在的心血管疾病易感性，如高血压、中年人和阻塞性睡眠呼吸暂停。的 整个团队在昼夜节律、睡眠、压力、运动和CV生理学以及正电子发射方面拥有专业知识 静息状态下左心室肾上腺素能功能突触前和突触后平衡的断层成像 人类调查人员将使用出色的专用设施进行必要的密集，多- 白天的研究与护理，生物营养和临床支持服务与团队的生理整合 专业知识Shea博士拥有超过30年的临床研究经验，主要集中在昼夜节律方面 在健康人群中及其对CV疾病风险因素的影响，他已经完成了大部分CV研究。 使用经过验证的昼夜节律协议进行人体生理学研究。谢伊博士已经有了25个 连续几年作为首席执行官发起的联邦赠款。Shea博士的出版物被广泛引用， 过去十年[2009-18]原创研究论文的相对引用率为3.84，高于 同一领域所有NIH资助论文的90%百分位数[NIH Office of Portfolio Analysis：iCite Tool]）。由于 对整个身体昼夜节律的大小和范围的快速认识，包括 药物靶点的昼夜节律，我们正处于CV医学中有意义的昼夜节律试验的尖端， 考虑内部昼夜节律时间。本研究计划中进行的这些临床前研究将提供 充分利用这些机会改善CV疾病治疗所需的关键和及时的背景。

PROJECT SUMMARY/ABSTRACT Endogenous circadian clocks exist in all cells and tissues, including the autonomic nervous system, heart, and vasculature. The resultant rhythms prepare the cardiovascular (CV) system for optimal function to match the daily anticipated behavioral and environmental cycles, such as altered posture and increased activity after awakening in the morning. However, the morning is also the most vulnerable time for adverse CV events, including myocardial infarction, stroke and sudden cardiac death. Dr. Shea has pioneered the use of intensive, multi-day laboratory experiments and uncovered substantial endogenous circadian rhythms across the CV system in healthy humans. Dr. Shea also discovered that circadian rhythms exist in the CV reactivity to stressors (i.e., there are different CV responses to identical stressors at different times of day). Dr. Shea’s work has led to the concept that circadian rhythms in the CV system act as a ‘double-edged sword’: the normal amplified responses in the morning aid the transition from sleep to activity in healthy individuals, but such exaggerated responses are potentially perilous in individuals with underlying CV risk factors who are susceptible to adverse events. Dr. Shea will lead a multi-disciplinary team of outstanding investigators to examine the broad question of how the circadian system interacts with behavior-related CV responses to produce predictable daily variations in CV risk profiles. To compare with healthy controls, studies will be performed in populations with increased underlying susceptibility to CV disease, such as hypertension, midlife adults, and obstructive sleep apnea. The overall team has expertise in circadian, sleep, stress, exercise and CV physiology, and positron emission tomographic imaging of the balance of pre- and post-synaptic adrenergic function in the left ventricle in resting humans. The investigators will use outstanding purpose-built facilities to perform the necessary intensive, multi- day studies with nursing, bio-nutrition and clinical support services integrated with the team’s physiological expertise. Dr. Shea has >30 years’ experience performing clinical research mainly focused on circadian rhythms in healthy humans and their impact on CV disease risk factors, and he has performed the majority of the CV physiology studies in humans that use validated circadian protocols. Dr. Shea has been well-funded with 25 consecutive years as PI of investigator-initiated federal grants. Dr. Shea’s publications are well-cited with a mean relative citation ratio of 3.84 for original research papers in the past decade [2009-18], which is higher than the 90% percentile for all NIH-funded papers in the same field [NIH Office of Portfolio Analysis: iCite Tool]). Due to the fast emerging recognition of the magnitude and extent of circadian rhythms throughout the body, including circadian rhythms in drug targets, we are on the cusp of meaningful chronotherapeutic trials in CV medicine that consider internal circadian time. These preclinical studies performed in this Research Program will provide the critical and timely background needed to fully exploit these opportunities to improve therapy of CV disease.