Chronobiology of cardiovascular and pulmonary disease

描述（由申请人提供）：申请人有一个资助的研究计划在医学年表，是美国国立卫生研究院资助的哈佛大学睡眠，昼夜节律和呼吸神经生物学培训计划的副主任，并有良好的跟踪记录和承诺，指导临床研究人员在适当的情况下使用本培训计划提供的正式结构。候选人的目标是培养一批杰出的医学时间表临床研究人员-了解昼夜节律和睡眠/觉醒机制，这些机制是许多疾病严重程度的日/夜模式的基础。这项研究的环境是杰出的，有60多名成功的研究人员参与了哈佛大学睡眠医学部。有“最先进的”研究设施，包括在布莱根妇女医院的哈佛大学临床和转化科学中心（CTSC）的密集的生理监测套房。候选人目前有研究资金来确定健康年轻受试者的生物钟与心血管风险标志物行为的作用。为了了解这项工作的临床相关性，候选人希望将这些研究扩展到更脆弱的人群，如老年人，久坐不动，肥胖和高血压患者。在这些人群中，流行病学研究揭示了上午10点左右不良心血管事件的高频率。为了研究这种影响，将使用“强迫性强迫性”方案，其中受试者的行为发生在昼夜节律周期的所有阶段。目的是确定内在昼夜节律（独立于行为）对心血管风险标志物的影响以及昼夜节律系统与行为应激源（包括姿势变化、运动和精神压力）之间的任何相互作用。脆弱性的心血管标志物包括自主神经系统测量、脑血流自动调节、血小板聚集性和内皮功能。预期标准行为应激源（姿势、活动或睡眠/清醒状态的标准化变化）将在昼夜节律周期的特定阶段具有不同的影响-揭示昼夜节律系统对于某些行为的脆弱阶段。申请人的长期目标将是通过行为或时间药理学的改变来改善此类疾病的治疗。相关性（见说明）：许多疾病的严重程度在24小时内各不相同。例如，心脏病发作最常发生在早上醒来后几个小时，哮喘通常在晚上最严重。我们的目标是了解这些疾病严重程度随时间变化的生物学基础，这可能会导致更好的治疗（例如，针对生物钟的特定阶段或与导致脆弱性的特定行为相一致的适当定时药物）。 (End摘要）

DESCRIPTION (provided by applicant): The applicant has a funded research program in medical chronoblology, is Associate Director of an NIH funded Harvard-wide Training Program in Sleep, Circadian & Respiratory Neurobiology, and has an excellent track record and commitment to mentoring clinical researchers using where appropriate the formal structure provided by this Training Program. The candidate's goal is to develop a group of outstanding clinical investigators of medical chronoblology - to understand the circadian and sleep/wake mechanisms underlying the day/night pattern in the severity of a number of disorders. The environment for this research is outstanding, with over 60 successful research faculty involved with the Harvard-wide Division of Sleep Medicine. There are 'state of the art' research facilities, comprising intensive physiological monitoring suites in Harvard University's Clinical and Translational Science Center (CTSC) at the Brigham & Women's Hospital site. The candidate has current research funding to determine the role of the body clock versus behaviors on cardiovascular risk markers in healthy young subjects. To understand the clinical relevance of this work, the candidate wishes to extend these studies to examine more vulnerable populations, such as elderly, sedentary, obese and hypertensive individuals. In these groups, epidemiological studies have revealed a high frequency of adverse cardiovascular events around 10 AM. To study such effects, a "Forced Desynchrony" protocol will be used, wherein subjects' behaviors occur at all phases of the circadian cycle. The aims are to determine the effect upon cardiovascular risk markers of the intrinsic circadian rhythm (independent from behaviors) and any interaction between the circadian system and behavioral stressors, including postural changes, exercise and mental stress. Cardiovascular markers of vulnerability include autonomic nervous system measures, cerebral blood flow autoregulation, platelet aggregability and endothelial function. It is anticipated that standard behavioral stressors (standardized changes in posture, activity or sleep/wake state) will have different effects at specific phases of the circadian cycle - revealing vulnerable phases of the circadian system for certain behaviors. The applicant's longer term goals will be to improve therapy in such disorders via modifications in behavior or chronopharmacology. RELEVANCE (See instructions): The severity of many diseases varies across the 24-hour period. For example, heart attacks occur most frequently in the morning a few hours after waking up, and asthma is generally worst at night. We aim to understand the biological basis behind these time-variant changes in disease severity, which could lead to better therapy (e.g. appropriately timed medication to target specific phases of the body clock or to coincide with specific behaviors that cause vulnerability). (End of Abstract)