The Role of Circadian Periodicity in Human Cardiovascular Disease and Diabetes

昼夜节律在人类心血管疾病和糖尿病中的作用

• 批准号: 8248272
• 负责人: JOHN P FORMAN
• 金额: $ 67.38万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8248272
• 关键词: Affect; Antioxidants; Blood Vessels; Cardiovascular Diseases; Cells; Circadian Rhythms; Cross-Sectional Studies; Data; Data Collection; Development; Diabetes Mellitus; E-Selectin; Elements; Event; Fasting; Frequencies; Functional disorder; Future; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Heart; Hormones; Hour; Human; Human Genetics; Hypertension; Inflammation; Insulin; Insulin Resistance; Intercellular adhesion molecule 1; Interleukin-6; Life Style; Light; Link; Mediator of activation protein; Melatonin; Melatonin Receptors; Molecular; Myocardial Infarction; Nested Case-Control Study; Non-Insulin-Dependent Diabetes Mellitus; Nurses' Health Study; Pacemakers; Pancreas; Pathogenesis; Periodicity; Peripheral; Phase; Pineal gland; Prevalence; Prevention; Prevention strategy; Production; Relaxation; Reporting; Research Design; Risk; Role; Sleep; Sleep Deprivation; Snoring; Stroke; Structure of beta Cell of islet; System; Testing; Urine; Variant; Woman; cardiovascular disorder risk; case control; circadian pacemaker; cohort; cost effective; gene environment interaction; genetic association; genetic variant; human disease; human tissue; indexing; inflammatory marker; innovation; insulin secretion; insulin sensitivity; novel; programs; prospective; public health relevance; research study; shift work; suprachiasmatic nucleus; treatment strategy

DESCRIPTION (provided by applicant): Several lines of evidence point toward circadian involvement in the pathogenesis of human disease. The human circadian system consists of a central pacemaker (suprachiasmatic nucleus) and also peripheral oscillators that are located in nearly every human tissue, including the heart, vessel walls and beta cells of the pancreas. Melatonin is a hormone secreted by the pineal gland (under the control of the suprachiasmatic nucleus) and entrained to the dark phase of a light-dark cycle. Besides serving as an antioxidant, melatonin suppresses sympathetic outflow, promotes vascular relaxation, and affects insulin secretion. As a molecular mediator of the circadian clock, melatonin is inversely associated with the development of hypertension in prospective data, and inversely associated with the prevalence of cardiovascular disease (CVD) in cross- sectional studies; furthermore, polymorphisms in the melatonin receptors are associated with type 2 diabetes mellitus (T2DM). Whether melatonin production is independently associated with future CVD events and incident T2DM, however, has not been studied. Although human genetic studies suggest that common variants in core genes that control the circadian system (e.g., clock, arntl) may influence the development of T2DM and hypertension, associations with CVD have not been reported, and potential interactions between circadian disruption (short sleep duration, rotating night shift work, snoring) and these variants have not been explored. Finally, the relation between elements of the circadian system (i.e., melatonin, circadian genes) and CVD/T2DM mediators in humans is not well understood. The 3 major hypotheses that we will investigate are: (1) lower melatonin production is associated with CVD (myocardial infarction [MI] and stroke) and T2DM; (2) common variants in circadian genes are associated with CVD and T2DM, and the association is modified by circadian-disruptive factors; and (3) both lower melatonin production and circadian gene variants are associated with inflammation, insulin resistance, and endothelial dysfunction. In this study, we propose to draw on both new data collection and extensive existing genetic data from the ongoing Nurses' Health Study (NHS) cohort. Aim 1 will employ two nested case-control studies (400 case-control pairs each) to examine the prospective association between melatonin production and the risk of incident CVD and T2DM events. Aim 2 will employ a large sub-cohort (N=11,587) to investigate whether common genetic variants in circadian control genes are associated with prevalent CVD and T2DM, and prospectively, whether these variants interact with short sleep duration, rotating night shift work, and snoring in the development of CVD and T2DM. Aim 3 will examine whether elements of the circadian system (melatonin, genetic variants) are associated with inflammation, insulin resistance, and endothelial dysfunction. The results from this highly efficient and cost- effective study will help elucidate the relation between circadian misalignment and CVD and T2DM, and ultimately, could help identify novel treatment and prevention strategies. PUBLIC HEALTH RELEVANCE: Several lines of evidence point toward involvement of circadian rhythms (that is, the human day-night cycle) in the development of heart attacks, strokes, and diabetes. This study aims to elucidate the role of human circadian elements, specifically melatonin (the nighttime hormone) plus genes that control the circadian system, in the development of cardiovascular disease and diabetes, as well as to determine whether there is an interplay between these circadian elements and lifestyle-induced circadian disruption (like sleep deprivation and snoring). Our project may help provide a framework for innovative approaches in cardiovascular disease and diabetes treatment and prevention.

描述（由申请人提供）：几条证据表明昼夜节律参与了人类疾病的发病机理。人类昼夜节律系统由一个中央起搏器（上核）以及位于几乎每个人体组织（包括心脏，容器壁和胰腺的β细胞）中的外周振荡器组成。褪黑激素是一种由松果体分泌的激素（在上核的控制下），并被带入光黑暗循环的暗相。除了用作抗氧化剂外，褪黑激素还抑制交感神经流出，促进血管松弛并影响胰岛素分泌。作为昼夜节律时钟的分子介体，褪黑激素与前瞻性数据中高血压的发展成反比，并且与横断研究中心血管疾病（CVD）的患病率成反比。此外，褪黑激素受体中的多态性与2型糖尿病（T2DM）有关。但是，尚未研究褪黑激素的生产与未来的CVD事件和事件T2DM独立相关。尽管人类遗传研究表明，控制昼夜节律系统的核心基因中的常见变异（例如，时钟，ARNTL）可能会影响T2DM和高血压的发展，尚未报告与CVD的关联，并且昼夜节律中断（短睡眠持续时间，旋转的夜班工作，snornor，snoring，snoring，snoring）以及这些变异的潜在相互作用。最后，人类中昼夜节律系统（即褪黑激素，昼夜节律基因）和CVD/T2DM介体的元素之间的关系尚不清楚。我们将研究的3个主要假设是：（1）褪黑激素的产生与CVD（心肌梗塞[MI]和中风）和T2DM有关； （2）昼夜节律基因中的常见变体与CVD和T2DM相关，并且通过昼夜节律中断的因素进行了修改； （3）较低的褪黑激素产生和昼夜节律变体都与炎症，胰岛素抵抗和内皮功能障碍有关。在这项研究中，我们建议从正在进行的护士健康研究（NHS）同类中的新数据收集和广泛的现有遗传数据借鉴。 AIM 1将采用两项嵌套的病例对照研究（每条400个病例对照对），以检查褪黑激素生产与发生CVD和T2DM事件的风险之间的前瞻性关联。 AIM 2将采用大型亚果园（n = 11,587）来研究昼夜节律控制基因中常见的遗传变异是否与普遍存在的CVD和T2DM相关，并且前瞻性地，这些变体是否与短睡眠持续时间相互作用，旋转夜班工作以及在CVD和T2DM的开发中sn着。 AIM 3将检查昼夜节律系统（褪黑激素，遗传变异）的元素是否与炎症，胰岛素抵抗和内皮功能障碍有关。这项高效且具有成本效益的研究的结果将有助于阐明昼夜节律未对准与CVD和T2DM之间的关系，最终可以帮助确定新颖的治疗和预防策略。 公共卫生相关性：几条证据表明，昼夜节律参与心脏病发作，中风和糖尿病的发展。这项研究旨在阐明人类昼夜节律元素的作用，特别是褪黑激素（夜间激素）以及控制昼夜节律系统的基因，在心血管疾病和糖尿病的发展中，以及确定这些昼夜节律元素和生活方式诱导的剥夺的剥夺和sneperivation和sne snecrivation和Snoresy诱导的剥夺和sn snoresy helectian元素之间是否存在相互作用。我们的项目可能有助于为心血管疾病和糖尿病治疗和预防的创新方法提供框架。