Mechanisms Linking Sleep-Disordered Breathing and Cardiovascular Disease

描述（由申请人提供）：本申请涉及广泛的挑战领域（04）临床研究和特定的挑战主题，04- hl - 101：识别心肺疾病风险和睡眠呼吸障碍（SDB）的联系机制。SDB是一种常见病，大约5%的中老年人受其影响。其特点是睡眠时上呼吸道反复塌陷，伴有间歇性低氧血症和反复觉醒。过去几年的研究表明，SDB与高血压和心血管疾病独立相关。然而，这些关联背后的因果机制尚不清楚。间歇性低氧血症是SDB的一种病理特征，已知可触发包括内皮素-1 （ET-1）在内的一系列信号通路，并增加胰岛素抵抗、葡萄糖耐受不良和2型糖尿病的倾向。本提案的总体目标是表征SDB可能导致葡萄糖代谢改变的机制，并确定ET-1可能的作用。为了实现我们的目标，我们将采用独特的观察性和介入性人体研究，体内和体外间歇性缺氧方案，以及分子生物学方法来阐明间歇性缺氧对葡萄糖代谢的直接影响。我们的具体目标如下。目的1：探讨SDB和间歇性缺氧对胰岛素敏感性、胰岛素分泌和循环ET-1水平的影响。我们将证明：(a) SDB患者的ET-1水平会升高，这些水平将由夜间低氧血症的程度决定，并预测胰岛素抵抗的严重程度和胰岛素分泌受损；(b)在正常受试者中，暴露于短期间歇性缺氧会增加ET-1并损害胰岛素敏感性和分泌。目的2：确定间歇性缺氧诱导的ET-1通路的改变是否有助于胰岛素敏感性和分泌的改变。我们假设，在小鼠模型中，暴露于间歇性缺氧会：(a)降低胰岛素敏感性和胰岛素分泌；(b)增加循环ET-1水平；(c) ET-1受体拮抗剂可防止缺氧引起的葡萄糖代谢改变。目的3：评估间歇性缺氧是否对胰岛细胞功能产生直接影响，以及这是否由ET-1介导。我们假设胰岛素分泌将：(a)暴露于间歇性缺氧会受损，(b)在ET-1拮抗剂存在的情况下间歇性缺氧不会改变。本应用程序中概述的实验将为SDB与代谢功能障碍和心血管疾病之间的因果关系提供重要的机制见解。影响：约翰霍普金斯大学每年在马里兰州直接创造约100亿美元的经济活动，比2002年的70亿美元增长了43%，相当于今天该州经济中每24美元中就有1美元。2008年，约翰霍普金斯大学提供了4.5万个就业岗位，自2002年以来，每年创造700个新就业岗位。约翰霍普金斯大学直接或间接地为马里兰州提供了超过10万个就业岗位，占该州每29个就业岗位的1个。仅在巴尔的摩市，约翰霍普金斯大学就直接或间接地提供了6万个就业岗位，占全市就业岗位的16.7%。此应用程序将创建三个作业。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (04) Clinical Research and specific Challenge Topic, 04-HL- 101: Identifying Mechanisms Linking Cardiopulmonary Disease Risk and Sleep-Disordered Breathing (SDB). SDB is a common condition that affects approximately 5% of all middle-aged and older adults. It is characterized by recurrent collapse of the upper airway during sleep and is associated intermittent hypoxemia and recurrent arousals. Research over the last few years has shown that SDB is independently associated hypertension and cardiovascular disease. However, causal mechanisms underlying these associations are still not clear. Intermittent hypoxemia, a pathognomonic feature of SDB, is known to trigger a cascade of signaling pathways including endothelin-1 (ET-1) and increasing the propensity for insulin resistance, glucose intolerance and type 2 diabetes. The overarching goal of this proposal is to characterize the mechanisms through which SDB may lead to alterations in glucose metabolism and determine the putative role of ET-1. To accomplish our goals, we will employ a combination of unique observational and interventional human studies, in vivo and ex vivo intermittent hypoxia protocols, and molecular biological approaches to elucidate the direct effects of intermittent hypoxia on glucose metabolism. Our specific aims are as follows. AIM 1: To determine the effects of SDB and intermittent hypoxia on insulin sensitivity, insulin secretion and circulating ET-1 levels. We will demonstrate that: (a) ET-1 levels will be elevated in patients with SDB and that these levels will be determined by the degree of nocturnal hypoxemia and predict the severity of insulin resistance and impaired insulin secretion; and (b) exposure to short-term intermittent hypoxia, in normal subjects, will increase ET-1 and impair insulin sensitivity and secretion. AIM 2: To determine whether intermittent hypoxia-induced changes in the ET-1 pathway contribute to alterations in insulin sensitivity and secretion. We hypothesize that, in a murine model, exposure to intermittent hypoxia will: (a) decrease insulin sensitivity and insulin secretion; (b) increase circulating ET-1 levels; (c) ET-1 receptor antagonists will prevent hypoxia-induced alterations in glucose metabolism. AIM 3: To evaluate whether intermittent hypoxia exerts a direct effect on islet cell function and whether this is mediated by ET-1. We hypothesize that insulin secretion will be: (a) impaired by exposure to intermittent hypoxia, and (b) unaltered by intermittent hypoxia in the presence of ET-1 antagonists. The experiments outlined in this application will provide important mechanistic insight into the causal pathways that may link SDB and metabolic dysfunction and cardiovascular disease. IMPACT: Every year Johns Hopkins Institutions directly generate about $10 billion in economic activity in the State of Maryland, a 43% increase from the $7 billion generated in 2002 and the equivalent of one of every twenty-four dollars in the state's economy today. In 2008, Johns Hopkins Institutions provided 45,000 jobs and created 700 new jobs each year since 2002. Directly and indirectly Johns Hopkins Institutions support more than 100,000 jobs in Maryland, one of every 29 in the state. In Baltimore City alone Johns Hopkins directly and indirectly supports 60,000 jobs, or 16.7% of all City employment. This application will create three jobs. PUBLIC HEALTH RELEVANCE: Sleep-disordered breathing is a common condition that affects more than 12 million adults in the US and has been associated with daytime sleepiness, high blood pressure, cardiovascular disease, and diabetes. The overall objective of this research proposal is to determine how sleep-disordered breathing leads to insulin resistance and defects in insulin secretion from the pancreas, which in turn can increase the future risk for cardiovascular disease.