Pathogenesis and Genetics of Obstructive Sleep Apnea

虽然睡眠障碍已被美国国立卫生研究院确定为一个具有巨大科学增长潜力的领域，但以患者为导向的研究睡眠相关问题的研究人员却很少。宾夕法尼亚大学有幸拥有国际公认的师资队伍和强大的基础设施，以支持高质量的以患者为导向的睡眠障碍研究和培训。该基础设施包括：睡眠和呼吸神经生物学中心、临床流行病学和生物统计学中心、普通临床研究中心、3个睡眠训练补助金和肺成像组。Schwab博士是这些项目中不可或缺的一部分，并高度致力于以患者为导向的睡眠研究事业，建议研究阻塞性睡眠呼吸暂停的遗传学和生物力学基础。Schwab博士对睡眠呼吸暂停患者上呼吸道的变化进行了开创性的观察，他成功地指导了几位肺科研究员和初级教员。通过K24的资助，Schwab博士可以进一步发展成为一名学术领袖，并培养睡眠领域急需的其他研究人员。具体来说，该奖项将允许Schwab博士在上呼吸道成像和基于计算机的体积分析的新放射技术方面发展进一步的专业知识；进一步他在遗传流行病学和生物信息学方面的专业知识；增加指导年轻科学家和发展与科学家合作的新领域的时间。Schwab博士开发了一个最先进的上呼吸道成像项目，专注于了解阻塞性睡眠呼吸暂停的发病机制和治疗。最近，Schwab博士已经开始运用他的上呼吸道成像专业知识来研究睡眠呼吸暂停的表型危险因素。他是第一个应用先进的定量磁共振成像技术和新的体积计算机图像分析技术来研究睡眠呼吸暂停的遗传基础。这项拨款的科学部分将利用上呼吸道成像来研究睡眠呼吸暂停的发病机制和遗传学。我的具体目标是：1)评估和比较呼吸暂停和正常体重匹配的对照组在清醒和睡眠期间的上呼吸道软组织结构和生物力学特性；2)使用三维磁共振成像量化上呼吸道颅面结构、软组织和区域脂肪沉积，以确定与阻塞性睡眠呼吸暂停相关的中间特征，采用正常人和呼吸暂停患者的病例对照设计；3)通过比较先证者、先证者的兄弟姐妹、邻居对照者和邻居对照者的兄弟姐妹，确定睡眠呼吸暂停的上呼吸道结构风险因素，这些因素表现出家庭聚集性，最有可能具有遗传成分。为了解决这些特定的目标，我们计划了一系列合乎逻辑的研究，这些研究将为阻塞性睡眠呼吸暂停的发病机制和这种情况的解剖学危险因素提供见解。

Although sleep disorders have been identified by the NIH as an area with tremendous scientific growth potential there are a paucity of patient oriented investigators studying sleep-related questions. The University of Pennsylvania is fortunate to have internationally recognized faculty and a strong infrastructure to support high quality patient-oriented research and training m sleep disorders. This infrastructure includes: Center for Sleep and Respiratory Neurobiology, Center for Clinical Epidemiology and Biostatistics, General Clinical Research Center, 3 Sleep Training Grants and the Pulmonary Imaging Group. Dr. Schwab is an integral part of each of these programs and is highly committed to a career in patient-oriented sleep research, proposing to study the genetics and biomechanical basis for obstructive sleep apnea. Dr. Schwab has made seminal observations about changes in the upper airway in patients with sleep apnea and he has successfully mentored several pulmonary fellows and junior faculty. Dr. Schwab through funding from this K24 can further develop into an academic leader and train others investigators that the sleep field desperately needs. Specifically this award would allow Dr. Schwab to develop further expertise in new radiologic techniques in upper airway imaging and computer-based volumetric analysis; further his expertise in genetic epidemiology and bioinformatics; allow increased time for mentoring young scientists and for developing new areas of collaboration with scientists. Dr. Schwab has developed a state-of-the-art upper airway imaging program focusing on understanding the pathogenesis and treatment of obstructive sleep apnea. Recently, Dr. Schwab has begun to apply his upper airway imaging expertise to study phenotypic risk factors for sleep apnea. He is the first to apply advanced quantitative MR Imaging techniques and novel volumetric computer image analysis techniques to study the genetic basis for sleep apnea. The scientific portion of this grant will utilize upper airway imaging to study both the pathogenesis and genetics of sleep apnea. My specific aims are: 1) to evaluate and compare upper airway soft tissue structural and biomechanical properties in apneics and normal weight-matched controls during wakefulness and sleep; 2) to quantify upper airway craniofacial structure, soft tissues and regional fat deposition using three dimensional magnetic resonance imaging in order to determine the intermediate traits associated with obstructive sleep apnea utilizing a case control design in normals and apneics ; and 3) to determine the upper airway structural risk factors for sleep apnea that demonstrate family aggregation and are most likely to have a genetic component by comparing probands, siblings of probands, neighborhood controls and siblings of neighborhood controls. To address these specific aims, we have planned a logical series of studies that will provide insight in the pathogenesis of obstructive sleep apnea and the anatomic risk factors for this condition.