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Mechanisms Linking Sleep-Disordered Breathing and Cardiovascular Disease

睡眠呼吸障碍与心血管疾病之间的联系机制

基本信息

批准号：
7937081
负责人：
Naresh M Punjabi
金额：
$ 50万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7937081
关键词：
Address Adult Adverse effects Affect Animal Model Apnea Area Arousal Baltimore Biological Cardiovascular Diseases Cell Survival Cell physiology Cities Clinical Clinical Research Data Defect Development Diabetes Mellitus Drops Economics Elderly Employment Endothelin A Receptor Endothelin-1 Event Exposure to Functional disorder Future Glucose Intolerance Goals Human Hyperinsulinism Hypertension Hypoxemia Hypoxia Institution Insulin Insulin Resistance Islet Cell Laboratories Lead Link Maryland Mediating Mediator of activation protein Metabolic Modeling Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Occupations Oxyhemoglobin Pancreas Pathway interactions Patients Peptides Play Predisposition Protocols documentation Pulmonary Heart Disease Recurrence Relative (related person)Request for Proposals Research Research Proposals Risk Factors Role Severities Signal Pathway Sleep Sleep Apnea Syndromes Sleep Fragmentations Work base blood glucose regulation cardiovascular disorder risk clinically relevant disorder risk glucose metabolism improved in vivo insight insulin secretion insulin sensitivity middle age nocturnal Hypoxemia prevent public health relevance receptor research study translational approach

项目摘要

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.

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：确定心脏病风险与睡眠呼吸障碍（SDB）之间的联系机制。SDB是一种常见的疾病，影响大约5%的中年和老年人。其特征是睡眠期间上呼吸道反复塌陷，并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仍然不清楚。间歇性低氧血症是SDB的一种特异性特征，已知可触发包括内皮素-1（ET-1）在内的信号传导通路级联反应，并增加胰岛素抵抗、葡萄糖耐受不良和2型糖尿病的倾向。该建议的总体目标是表征SDB可能导致葡萄糖代谢改变的机制，并确定ET-1的假定作用。为了实现我们的目标，我们将采用独特的观察性和干预性人体研究，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：观察SDB和间歇性低氧对胰岛素敏感性、胰岛素分泌和循环内皮素（ET-1）水平的影响。我们将证明：（a）SD B患者的ET-1水平将升高，这些水平将由夜间低氧血症的程度决定，并预测胰岛素抵抗和胰岛素分泌受损的严重程度;和（B）在正常受试者中，暴露于短期间歇性低氧将增加ET-1并损害胰岛素敏感性和分泌。目的2：探讨间歇性低氧诱导的ET-1通路变化是否与胰岛素敏感性和分泌有关。我们假设，在小鼠模型中，暴露于间歇性缺氧将：（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受体拮抗剂将防止缺氧诱导的葡萄糖代谢改变。目的3：探讨间歇性低氧对胰岛细胞功能的直接影响及其是否通过内皮素1（ET-1）介导。我们假设胰岛素分泌将：（a）暴露于间歇性缺氧而受损，（B）在ET-1拮抗剂存在下不受间歇性缺氧的影响。本申请中概述的实验将为可能将SDB与代谢功能障碍和心血管疾病联系起来的因果途径提供重要的机制见解。影响：每年约翰霍普金斯学院直接在马里兰州产生约100亿美元的经济活动，比2002年产生的70亿美元增加了43%，相当于今天该州经济中的每24美元。2008年，约翰霍普金斯机构提供了45，000个工作岗位，自2002年以来每年创造700个新工作岗位。约翰·霍普金斯大学直接和间接地为马里兰州提供了超过100，000个就业岗位，占该州每29个就业岗位中的一个。仅在巴尔的摩市，约翰霍普金斯大学就直接和间接提供了6万个工作岗位，占该市所有就业岗位的16.7%。该应用程序将创建三个工作岗位。公共卫生关系：睡眠呼吸障碍是一种常见的疾病，在美国影响超过1200万成年人，并与白天嗜睡，高血压，心血管疾病和糖尿病有关。这项研究提案的总体目标是确定睡眠呼吸障碍如何导致胰岛素抵抗和胰腺胰岛素分泌缺陷，从而增加未来心血管疾病的风险。