Mentored Patient Oriented Research in Sleep and Metabolic Disease

 描述(由申请人提供)：近期目标：研究阻塞性睡眠呼吸暂停(OSA)作为糖尿病心血管危险因素的作用，长期目标是评估在2型糖尿病患者群体中筛查和治疗OSA的相关性。职业发展目标：为指导提供足够的时间，并在指导方面发展更多的技能。研究项目：尽管2型糖尿病的心血管疾病管理有所改善，但其患病率仍然高得令人无法接受，而最近的许多研究表明，血糖控制超过一定程度的改善对大血管并发症的影响很小。这导致有人建议，针对并存疾病，如OSA，可能是努力降低糖尿病心血管风险的新前沿。在动物模型和人体研究中的研究表明，OSA是心血管疾病的独立危险因素。初步数据表明，阻塞性睡眠呼吸暂停综合征和糖尿病之间至少存在相加的相互作用，如果不是协同作用的话，但在得出可靠的结论之前，需要更详细地探讨另一种假设，即这两种疾病可能相互抵消或风险可能受到上限效应的限制。目前应用的主要假设是OSA和糖尿病协同增加内皮功能障碍，从而增加心血管疾病的风险。我们还假设，适当的OSA治疗将改善糖尿病人群的微循环和大循环中的血管功能。我们将首先评估2型糖尿病患者、单纯OSA患者、2型糖尿病合并OSA患者和健康对照组的心血管健康状况，包括心室重量、主动脉弹性、臂动脉反应性和微血管血流，以检验这些假设。接下来，我们将评估2型糖尿病合并阻塞性睡眠呼吸暂停患者随机接受3个月积极与安慰剂持续正压气道正压治疗的心血管结果。最后，我们将通过研究蛋白酪氨酸磷酸酶1b(PTP1B)途径的表达和激活来探索OSA影响糖尿病患者心血管功能的潜在细胞机制。

 DESCRIPTION (provided by applicant): Immediate Goals: To examine the role of obstructive sleep apnea (OSA) as a cardiovascular risk factor in diabetes with a long term goal of assessing the relevance of screening and treating OSA in type 2 diabetes patient populations. Career Development Goals: To provide sufficient time for mentoring and develop further skills in mentoring. Research Project: Despite improvements in the management of cardiovascular disease in type 2 diabetes, its prevalence remain unacceptably high while numerous recent studies have indicated that improvements of glycemic control beyond a certain point have minimal, if any, effects on macro-vascular complications. This has led to the suggestion that targeting coexisting conditions, such as OSA, may be the new frontier in the effort to reduce cardiovascular risk in diabetes. Studies in animal models as well as human studies demonstrate that OSA is an independent risk factor for cardiovascular disease. Preliminary data suggest there is at least an additive if not synergistic interaction between OSA and diabetes, but before solid conclusions can be reached, the alternative hypothesis, namely that the two diseases may offset one another or that risk may be limited by ceiling effects needs to be explored in more detail. The main hypothesis of the current application is that OSA and diabetes synergistically increase endothelial dysfunction and as a result cardiovascular disease risk. We also hypothesize that appropriate treatment of OSA will improve vascular function in both the micro- and macro-circulation in a diabetic population. We will test these hypotheses by first assessing cardiovascular health including ventricular mass, aortic elasticity, brachial artery reactivity, an micro-vascular flow cross-sectionally in subjects with type 2 diabetes alone, OSA alone, type 2 diabetes plus OSA, and healthy controls. Next, we will assess the same cardiovascular outcomes in a population with type 2 diabetes plus OSA randomized to 3 months of OSA therapy with active versus placebo treatment using continuous positive airway pressure. Finally, we will explore potential cellular mechanisms for OSA to impact cardiovascular function in diabetic patients by exploring expression and activation of the protein tyrosine phosphatase 1b (PTP1B) pathway.