The Impact of Obstructive Sleep Apnea on Non-Alcoholic Fatty Liver Disease

简介（由申请人提供）：Kathleen E. Corey，医学博士，公共卫生硕士，马萨诸塞州总医院（MGH）胃肠科教员，哈佛医学院（HMS）医学讲师。Corey博士在以患者为导向的研究，胃肠病学和肝病学方面具有背景。她的研究重点是脂质代谢与慢性肝病，特别是丙型肝炎和非酒精性脂肪性肝病（NAFLD）之间的相互作用。她在这些领域的工作产生了8篇第一作者出版物，包括鉴定NAFLD的两种脂质生物标志物，氧化低密度脂蛋白（OxLDL）和非高密度脂蛋白胆固醇。此外，她最近的研究评估了NAFLD发展的保护因素，她发现阻塞性睡眠呼吸暂停（OSA）是肥胖患者正常肝脏组织学的最强预测因素之一，这表明OSA可能在NAFLD的发展中发挥作用。阻塞性睡眠呼吸暂停和NAFLD都是重要的公共卫生状况。30%的美国人患有NAFLD，可导致肝硬化和肝细胞癌。据估计，超过1200万美国人患有阻塞性睡眠呼吸暂停症，这会加重代谢疾病，增加心血管疾病和猝死的风险。对这些疾病及其相互作用的研究将导致新的治疗选择和改善公共卫生结果。利用从这些研究中获得的知识，科里博士的建议将侧重于测试三个假设；1) OSA与NAFLD患病率增加有关，2)OSA与NAFLD之间的相互作用是由OxLDL测量的脂质过氧化介导的，3)NAFLD患者的OSA治疗将改善脂肪变性。虽然动物研究已经发现慢性间歇性缺氧、OSA的实验模拟和NAFLD之间有很强的关系，但人类研究受到方法学问题的限制，导致结果不确定。为了完成这项提议，Corey博士需要在研究设计、统计分析和阻塞性睡眠呼吸暂停机制方面接受额外的培训。Corey博士将受益于她的两位共同导师Raymond Chung博士和Atul Malhotra博士的指导，Raymond Chung博士是肝病学领域的知名基础和临床研究员，Atul Malhotra博士是OSA研究领域的知名内科科学家。Drs。Chung和Malhotra在指导临床研究人员方面建立了良好的记录，两人都获得了NIH K24奖。Corey博士还将接受Steven Grinspoon博士和Shiva Gautam博士的指导，Steven Grinspoon博士是一位成熟的代谢研究研究者和K24接受者，Shiva Gautam博士是一位经验丰富的生物统计学家和导师。她将接受哈佛医学院医学硕士项目在研究设计、高级生物统计学和预测建模方面的正式教学培训。她还将在哈佛-麻省理工学院健康科学与技术学院接受OSA病理生理学方面的培训，由她的共同导师Malhotra博士领导。有了这种额外的教育和指导，以及MGH提供的支持环境，Corey博士将很好地完成这项建议，并发展成为一名独立的临床研究者。

DESCRIPTION (provided by applicant): Kathleen E. Corey, MD, MPH is a member of the faculty of the Gastrointestinal Division of Massachusetts General Hospital (MGH) and an instructor in medicine at Harvard Medical School (HMS). Dr. Corey has a background in patient oriented research, gastroenterology and hepatology. Her research has focused on the interaction between lipid metabolism and chronic liver disease, specifically hepatitis C and non-alcoholic fatty liver disease (NAFLD). Her work in these areas has resulted in 8 first author publications including the identification of a two lipid biomarkers, oxidized low density lipoproteins (OxLDL) and non-high density lipoprotein cholesterol for NAFLD. In addition, her recent study assessing protective factors for the development of NAFLD, she found that obstructive sleep apnea (OSA) was one of the strongest predictors of normal liver histology in patients with obesity, suggesting that OSA may play a role in NAFLD development. Both OSA and NAFLD are important public health conditions. NAFLD affects 30% of Americans and can lead to cirrhosis and hepatocellular carcinoma. More than 12 million Americans are estimated to suffer from OSA which worsens metabolic disease and increases the risk of cardiovascular disease and sudden death. The study of these conditions and their interactions will lead to new treatment options and improved public heath outcomes. Using knowledge gained from these studies, Dr. Corey's proposal will focus on testing three hypotheses; 1) OSA is associated with an increased prevalence of NAFLD, 2) The interaction between OSA and NAFLD is mediated by lipid peroxidation as measured by OxLDL and 3) Treatment of OSA in patients with NAFLD will improvement in steatosis. While animal studies have found a strong relationship between chronic intermittent hypoxia, the experimental mimic of OSA, and NAFLD, human studies have been limited by methodologic issues leading to inconclusive results. To complete this proposal Dr. Corey will require additional training in study design, statistical analysis and obstructive sleep apnea mechanics. Dr. Corey will benefit from the guidance of her two co-mentors, Dr. Raymond Chung, an established basic and clinical investigator in hepatology and Dr. Atul Malhotra, an established physician-scientist in the study of OSA. Both Drs. Chung and Malhotra have established track records in the mentoring of clinical investigators and both hold NIH K24 awards. Dr. Corey will also receive mentoring from Dr. Steven Grinspoon, an established investigator in metabolic studies and K24 recipient and Dr. Shiva Gautam, an experience biostatistician and mentor. She will receive formal didactic training in study design, advanced biostatistics, and predictive modeling from the Master in Medical Science Program at Harvard Medical School. She will also receive training in OSA pathophysiology through courses at Harvard- Massachusetts Institute of Technology Health Sciences and Technology, lead by her co-mentor, Dr. Malhotra. With this additional education and guidance, as well as the supportive environment provided by the MGH, Dr. Corey will be well poised to complete this proposal and develop into an independent clinical investigator.