Pediatric Obstructive Sleep Apnea and Metabolic Syndrome

描述(由申请人提供)： 这项建议将通过导师、课程作业、研讨会和追求以患者为导向的研究项目，研究阻塞性睡眠呼吸暂停(OSAS)和代谢综合征之间的关系，为PI提供临床研究方面的正式和非正式教育。代谢综合征是2型糖尿病(T2 DM)和心血管疾病的先兆。与肥胖无关，OSAS是成人胰岛素抵抗和高血压的危险因素，这两个因素都是代谢综合征的组成部分。在成人OSAS中观察到内分泌系统和炎症标志物的变化，并可能直接导致代谢综合征，而脂肪组织中激素和细胞因子产生活跃的紊乱最近被认为与代谢综合征有关。儿童肥胖和T2 DM患病率的增加表明，OSAS也应该被评估为与儿童代谢综合征的联系。我们假设，儿童OSAS反复从睡眠和/或低氧血症中唤醒会导致炎症级联反应，包括脂肪因子的改变，以及交感神经输出的增加，这有助于血压升高和胰岛素敏感性降低，而OSAS的治疗逆转了这些干扰。我们将对患有和不患有OSAS的肥胖和非肥胖儿童进行多导睡眠图和详细的代谢研究，这些研究将在OSAS儿童治疗后重复进行，以达到我们的特定目标：1)确定OSAS儿童是否降低了与OSAS严重程度相关的胰岛素敏感性，2)确定OSAS儿童是否存在与胰岛素敏感性相关的循环炎症标志物增加、脂肪因子紊乱和儿茶酚胺分泌增加，以及3)确定OSAS的有效治疗是否逆转了胰岛素抵抗、代谢和炎症变化。PI的主要职业目标是成为一名具有儿科疾病内分泌共病专业知识的临床研究人员，她将利用这项研究作为职业发展的机制：1)通过与CHOP及其GCRC儿科临床研究的专家合作，巩固她作为临床研究人员的技能；2)参加宾夕法尼亚大学临床研究、药理学和神经生物学的正规教育；以及3)通过地方和国家会议继续进行糖尿病和内分泌学方面的教育。

DESCRIPTION (provided by applicant): This proposal will provide the PI formal and informal education in clinical research through mentors, course work, seminars, and the pursuit of a patient-oriented research project examining the relationship between obstructive sleep apnea (OSAS) and metabolic syndrome. Metabolic syndrome is a precursor to Type 2 diabetes (T2DM) and cardiovascular disease. Independent of obesity, OSAS is a risk factor in adults for insulin resistance and hypertension, both components of metabolic syndrome. Alterations in the endocrine system and in inflammatory markers have been observed in adult OSAS and may directly contribute to metabolic syndrome while disturbances in adipose tissue, active in both hormone and cytokine production, have recently been implicated in metabolic syndrome. The increasing prevalence of pediatric obesity and T2DM suggests OSAS should also be evaluated as a link to metabolic syndrome in children. We hypothesize that the repeated arousals from sleep and/or hypoxemia of pediatric OSAS lead to an inflammatory cascade, including alterations in adipokines, and enhanced sympathomimetic output which contribute to blood pressure elevations and decreased insulin sensitivity and that treatment of OSAS reverses these disturbances. We will perform polysomnography and detailed metabolic studies in obese and non-obese children with and without OSAS, and these studies will be repeated following treatment of children with OSAS to address our SPECIFIC AIMS: 1) To determine whether children with OSAS have decreased insulin sensitivity that correlates with severity of OSAS, 2) To determine whether children with OSAS have increased circulating inflammatory markers, disturbances in adipokines, and elevated catecholamine secretion that correlate with insulin sensitivity, and 3) To determine whether effective treatment of OSAS reverses insulin resistance, metabolic, and inflammatory changes. The PI, whose primary career goal is to become a clinical researcher with expertise in endocrine co-morbidities of pediatric disease, will use this study as a mechanism for career development: 1) to solidify her skills as a clinical investigator by working with experts in pediatric clinical research at CHOP and its GCRC, 2) to participate in formal education in clinical research, pharmacology, and neurobiology at The University of Pennsylvania, and 3) to continue education in diabetes and endocrinology through local and national conferences.