Individual Differences in Obstructive Sleep Apnea

描述（由申请人提供）： 睡眠呼吸暂停是一种系统性疾病。身体中的所有组织经历作为呼吸暂停的结果而发生的缺氧。因此，睡眠呼吸暂停会导致多种不良后果。睡眠呼吸暂停是可遗传的，尽管迄今为止还没有发现令人信服的基因变异。患者的风险和后果也存在重要的个体差异。这些个体差异表明，睡眠呼吸暂停是一种理想的疾病，可以制定个性化的风险评估，诊断和管理方法。正是这一总体概念推动了这一研究计划。该计划有3个项目和5个支持核心。第一个项目-阻塞性睡眠呼吸暂停（OSA）极端表型的机制（项目负责人：R。施瓦布）-专注于了解极端表型的基础。在这个项目中，研究人员研究了有和没有睡眠呼吸暂停的非常肥胖的个体。他们提出了这样一个问题：既然这些人有睡眠呼吸暂停的主要风险，那么什么可以保护那些没有这种疾病的人呢？这是脂肪分布的差异，不同的生理控制机制或组合？研究人员还研究了患有和不患有睡眠呼吸暂停综合症的瘦人，并提出了同样的问题--为什么？颅面结构、不同的脂肪分布和呼吸控制系统的不稳定性在瘦人呼吸暂停的发生中起什么作用？该项目是基于深入的表型。项目02-阻塞性睡眠呼吸暂停高血压个体差异的机制（项目负责人：S。Kuna）-解决了睡眠呼吸暂停的血压反应的个体差异的基础。研究人员提出，睡眠呼吸暂停对血压的最大影响将发生在降压药物不能控制血压的个体中，这些个体将从PAP治疗中获益最多。他们会问为什么？研究人员提出，血压反应的个体差异与睡眠呼吸暂停的氧化应激和儿茶酚胺反应的个体差异有关。他们预测，这些介质是由导致氧化应激的关键酶NADPH氧化酶的遗传差异驱动的，并提出了调节这种酶活性的基因测序。最后一个项目-睡眠呼吸暂停的遗传学及其后果（项目负责人：A。继续遗传主题，但提出了一种新的策略，以确定基因赋予睡眠呼吸暂停及其后果的风险。这一策略涉及小鼠，特别是遗传异质性远交小鼠，这是一种最近开发的，通过动物模型进行遗传发现的最先进方法，已经显示出其发现新遗传关联的能力。这些小鼠的高通量表型分型，连同全基因组SNP芯片的基因分型，允许鉴定与所研究的表型相关的小基因组区域。项目03中评估的表型为：舌脂肪（与项目01中的解剖结构相关）、对缺氧/高碳酸血症的缓解反应（与项目01中的生理机制相关）和对周期性间歇性缺氧的血压反应，类似于睡眠呼吸暂停中发生的血压反应（与项目02相关）。因此，所有三个项目协同工作。所有项目都由5个核心支持：a）行政，B）睡眠研究和招募，c）磁共振成像，d）分子评估，和e）生物统计学和数据管理。

DESCRIPTION (Provided by applicant): Sleep apnea is a systematic disorder. All tissues in the body experience hypoxia that occurs as a consequence of apneas. Thus, sleep apnea leads to multiple adverse consequences. Sleep apnea is heritable, although to date no convincing gene variants have been identified. There are also important individual differences in risks and consequences within patients. These individual differences suggest that sleep apnea is an ideal disorder to develop a PERSONALIZED approach to risk assessment, diagnosis and management. It is this overall concept that motivates this program of research. The program has 3 projects and 5 supporting cores. The first project-Mechanisms of Extreme Phenotypes in Obstructive Sleep Apnea (OSA) (Project Leader: R. Schwab)-is focused on understanding the basis of extreme phenotypes. In this project the investigators study very obese individuals with and without sleep apnea. They ask the question-given that these individuals have the major risk for sleep apnea, what protects those without the disorder? Is it a difference in fat distribution, different physiological control mechanisms or a combination? The investigators also study lean individuals with and without sleep apnea and ask the same question-why? What role does craniofacial structure, different distributions of fat and ventilatory control system instablity play in the development of apnea in thin individuals? This project is based on in-depth phenotyping. Project 02-Mechanisms for Individual Differences in Hypertension in Obstructive Sleep Apnea (Project Leader: S. Kuna)-addresses the basis of individual differences in blood pressure response to sleep apnea. The investigators propose that the largest effect of sleep apnea on blood pressure will occur in individuals whose BP is not controlled on anti-hypertensive medications, and that these individuals will benefit most from PAP treatment. They ask the question-why? The investigators propose that the individual differences in blood pressure response are related to individual differences in oxidative stress and catecholamine responses to sleep apnea. They predict that these proposed mediators are driven by genetic differences in the key enzyme that leads to oxidative stress-NADPH oxidase-and propose sequencing of genes that regulate activity of this enzyme. The final project-Genetics of Sleep Apnea and Its Consequences (Project Leader: A. Pack)-continues the genetic theme, but proposes a new strategy to identify genes conferring risk for sleep apnea and its consequences. This strategy involves mice, in particular the genetically heterogeneous Diversity Outbred mice, a recently developed, state-of-the-art approach to genetic discovery through animal models that has already shown its ability to discover new genetic associations. High throughput phenotyping of these mice, together with genotyping with a genome-wide SNP chip, allows identification of small genomic regions that relate to the phenotype being studied. The phenotypes being assessed in Project 03 are: tongue fat (relevant to anatomy in Project 01), ventilatory responses to hypoxia/hypercapnia (related to physiological mechanisms in Project 01), and blood pressure response to cyclical intermittent hypoxia, akin to that which occurs in sleep apnea (relevant to Project 02). Thus all 3 projects work synergistically. All projects are supported by 5 cores: a) Administrative, b) Sleep Study and Recruitment, c) Magnetic Resonance Imaging, d) Molecular Assessment, and e) Biostatistics and Data Management.