Non-Alcoholic Fatty Liver Disease and Obstructive Sleep Apnea: Mechanistic Links

描述(申请人提供)：非酒精性脂肪性肝病(NAFLD)是最常见的慢性儿科肝病，可能发展为侵袭性坏死性炎症性疾病(NASH)，导致多达三分之一的患者出现纤维化和硬化。NAFLD的发病机制复杂且尚未完全阐明。最近的证据表明，NASH和阻塞性睡眠呼吸暂停(OSA)之间存在潜在的联系，这两种疾病都是肥胖的常见共病。在这两种疾病中都会出现氧化应激增加和炎症标志物升高。暴露在间歇性低氧环境中的小鼠，如阻塞性睡眠呼吸暂停综合征，肝脏脂肪沉积增加。20-50%的成人阻塞性睡眠呼吸暂停患者血清转氨酶升高，经CPAP治疗后有所改善。到目前为止，研究NASH和OSA之间的关系的研究主要集中在气流受限，而不是更重要的生理意义上的低氧血症。因此，我们提出了一个新的假设，即OSA引起的慢性间歇性低氧血症通过启动氧化应激和上调炎症途径在NASH的发病机制中起关键作用。为了解决这一问题，我们提出了以下目标：1)确定OSA和夜间低氧血症是否与儿童NAFLD肝损伤的严重程度相关；2)确定反应性氧的产生是否与儿童NAFLD的低氧血症和肝损伤的严重程度相关；3)确定循环中的炎性介质是否与儿童NAFLD的低氧血症和肝损伤的严重程度相关。这将在活检证实为NAFLD的儿童中进行研究，他们将接受睡眠研究，并与患有OSA和/或低氧血症的对照组受试者进行比较。研究对象将接受血液和尿液测试，以寻找肝脏损伤、代谢异常、氧化应激和炎症途径激活的证据。纠正OSA/夜间低氧血症后，将评估肝损伤程度、氧化损伤和炎症途径激活的变化。作为对这一研究计划的补充，还提出了一项为期五年的有指导的职业发展计划，其中将包括授课和正式研究培训，由两名在儿科肝病、氧化剂损伤和低氧血症的临床和翻译研究方面具有专业知识的知名研究人员指导。候选人的主要职业目标是成为一名独立的临床/转化性研究人员，将确定儿童和青少年NAFLD的新机制和治疗方法。为了实现这一目标，应聘者制定了一项详细的计划，包括在免疫学、低氧血症和氧气感应、体内人体新陈代谢、遗传和分子流行病学以及纵向数据分析方面的进一步培训，并得到一个正式的职业发展咨询委员会的持续反馈。这项拟议的研究可能为儿童NASH潜在的肝损伤机制提供新的见解，并有可能转化为新的治疗和预防策略。

DESCRIPTION (provided by applicant): Non-alcoholic fatty liver disease (NAFLD) is the most common chronic pediatric liver disease and may progress to an aggressive necro-inflammatory disease (NASH) that leads to fibrosis and cirrhosis in up to 1/3 of affected individuals. The disease mechanisms leading to NAFLD pathogenesis are complex and incompletely understood. Recent evidence indicates a potential link between NASH and obstructive sleep apnea (OSA), both common co-morbidities of obesity. Increased oxidative stress and elevated inflammatory markers occur in both diseases. Mice exposed to intermittent hypoxia, such as occurs in OSA, develop increased hepatic fat deposition. Elevated serum aminotransferases are seen in 20-50% of adults with OSA, and improve with CPAP therapy. Studies to date examining the relationship between NASH and OSA have focused on airflow limitation rather than the more physiologically important hypoxemia. Therefore, we propose the novel hypothesis that chronic intermittent hypoxemia caused by OSA plays a key role in the pathogenesis of NASH through the initiation of oxidative stress and up regulation of inflammatory pathways. To address this, we propose the following Aims: 1) to determine if OSA and nocturnal hypoxemia are associated with increasing severity of liver injury in pediatric NAFLD, 2) to determine if reactive oxygen species generation is associated with hypoxemia and severity of liver injury in pediatric NAFLD and 3) to determine if circulating inflammatory mediators are associated with hypoxemia and severity of liver injury in pediatric NAFLD. This will be investigated in children with biopsy proven NAFLD who will undergo sleep study and control subjects with OSA and/or hypoxemia. Research subjects will undergo testing of blood and urine for evidence of liver injury, metabolic abnormalities, oxidative stress and activation of inflammatory pathways. Changes in the degree of liver injury, oxidant injury and activation of inflammatory pathways will be assessed after correction of OSA/nocturnal hypoxemia. Complimentary to this research program, a five year mentored career development program is proposed that will incorporate both didactic and formal research training guided by two well established investigators with expertise in clinical and translational research in pediatric liver disease, oxidant injury and hypoxemia. The candidate's overarching career goal is to become an independent clinical/translational investigator who will identify novel mechanisms and treatments of NAFLD in children and adolescents. To achieve this goal, the candidate has developed a detailed plan that includes further training in immunology, hypoxemia and oxygen sensing, in vivo human metabolism, genetic and molecular epidemiology and longitudinal data analysis, with ongoing feedback from a formal Career Development Advisory Committee. The proposed research may provide new insights into mechanisms underlying liver injury in pediatric NASH and potentially translate into novel therapeutic and preventive strategies.