Chronobiology of cardiovascular and pulmonary disease

申请人拥有医学年表学的资助研究项目，是NIH资助的哈佛范围内睡眠、昼夜节律和呼吸神经生物学培训项目的副主任，并有良好的记录和承诺指导临床研究人员使用该培训项目提供的适当的正式结构。该候选人的目标是培养一批杰出的医学年代学临床研究人员，了解许多疾病严重程度的昼夜节律和睡眠/觉醒机制。这项研究的环境非常出色，有超过60名成功的研究人员参与了哈佛大学的睡眠医学部门。这里有“最先进”的研究设施，包括位于布里格姆妇女医院的哈佛大学临床和转化科学中心（CTSC）的密集生理监测套件。该候选人目前已获得研究资金，以确定健康年轻受试者中生物钟与行为对心血管风险标志物的作用。为了了解这项工作的临床意义，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、肥胖和高血压个体。在这些人群中，流行病学研究显示，上午10点左右心血管不良事件的发生率很高。为了研究这种影响，将使用“强制去同步”协议，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压力源（包括姿势变化、运动和精神压力）之间的任何相互作用。心血管易损指标包括自主神经系统指标、脑血流自动调节、血小板聚集性和内皮功能。预计标准的行为压力源（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产生不同的影响，从而揭示昼夜节律系统中某些行为的脆弱阶段。申请人的长期目标将是通过改变行为或时间药理学来改善这些疾病的治疗。

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.