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

描述（由申请人提供）：非酒精性脂肪性肝病（NAFLD）是最常见的慢性儿科肝病，可能进展为侵袭性坏死性炎症性疾病（NASH），导致多达1/3的受影响个体发生纤维化和肝硬化。导致NAFLD发病机制的疾病机制是复杂的且不完全了解。最近的证据表明NASH和阻塞性睡眠呼吸暂停（OSA）之间存在潜在联系，两者都是肥胖的常见并发症。氧化应激增加和炎症标志物升高发生在这两种疾病中。小鼠暴露于间歇性缺氧，如发生在OSA，发展增加肝脏脂肪沉积。血清转氨酶升高见于20-50%的OSA成人，并通过CPAP治疗得到改善。迄今为止，研究NASH和OSA之间的关系的研究集中在气流限制，而不是更重要的生理低氧血症。因此，我们提出了一个新的假说，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通路在NASH的发病机制中起着关键作用。为了解决这个问题，我们提出了以下目的：1）确定OSA和夜间低氧血症是否与儿科NAFLD中肝损伤严重程度增加相关，2）确定活性氧物质的产生是否与儿科NAFLD中低氧血症和肝损伤严重程度相关，3）确定循环炎症介质是否与儿科NAFLD中低氧血症和肝损伤严重程度相关。这将在将接受睡眠研究的活检证实NAFLD儿童和OSA和/或低氧血症对照受试者中进行研究。研究受试者将接受血液和尿液检测，以确定肝损伤、代谢异常、氧化应激和炎症通路激活的证据。在OSA/夜间低氧血症纠正后，将评估肝损伤程度、氧化损伤和炎症通路活化的变化。作为对该研究计划的补充，提出了一项为期五年的指导性职业发展计划，该计划将由两名具有儿科肝病，氧化损伤和低氧血症临床和转化研究专业知识的成熟研究人员指导教学和正式研究培训。候选人的总体职业目标是成为一名独立的临床/翻译研究者，他们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，候选人制定了详细的计划，包括免疫学，低氧血症和氧传感，体内人体代谢，遗传和分子流行病学以及纵向数据分析的进一步培训，并从正式的职业发展咨询委员会获得持续的反馈。这项研究可能为儿童NASH肝损伤的机制提供新的见解，并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.