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

阻塞性睡眠呼吸暂停对非酒精性脂肪肝的影响

• 批准号: 8567780
• 负责人: Kathleen Elizabeth Corey
• 金额: $ 18.47万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8567780
• 关键词: Affect; American; Animals; Area; Behavior Therapy; Biological Markers; Biometry; Body Weight decreased; Chronic; Cirrhosis; Clinical; Clinical Investigator; Continuous Positive Airway Pressure; Development; Diabetes Mellitus; Education; Environment; Evaluation; Faculty; Functional disorder; Gastroenterology; General Hospitals; Health; Health Sciences; Health Technology; Hepatic; Hepatitis C; Hepatology; High Prevalence; Histologic; Histology; Human; Hypoxia; Institutes; Knowledge; Lead; Link; Lipid Peroxidation; Lipids; Liver; Liver diseases; Malignant neoplasm of liver; Massachusetts; Measures; Mechanics; Mediating; Mediator of activation protein; Medical; Medicine; Mentors; Metabolic Diseases; Metabolic syndrome; Mid-Career Clinical Scientist Award (K24); Obesity; Obstructive Sleep Apnea; Outcome; Participant; Pathology; Patients; Persons; Phospholipids; Physicians; Play; Polysomnography; Prevalence; Primary carcinoma of the liver cells; Public Health; Publications; Records; Research; Research Design; Research Personnel; Risk Factors; Role; Science; Scientist; Serum; Severities; Sleep; Sleep Apnea Syndromes; Staining method; Stains; Sudden Death; Technology; Testing; Training; United States National Institutes of Health; Vitamin E; Work; bariatric surgery; cardiovascular disorder risk; chronic liver disease; cohort; comparative effectiveness; density; disorder risk; effective therapy; effectiveness trial; experience; gastrointestinal; high risk; improved; instructor; lipid metabolism; lipoprotein cholesterol; liver transplantation; medical schools; member; metabolic abnormality assessment; mortality; non-alcoholic fatty liver; nonalcoholic steatohepatitis; oxidized lipid; oxidized low density lipoprotein; patient oriented research; predictive modeling; primary outcome; programs; public health relevance; therapy development

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.

描述（由申请人提供）：Kathleen E. Corey，医学博士、公共卫生硕士，是马萨诸塞州总医院 (MGH) 胃肠科的教员，也是哈佛医学院 (HMS) 的医学讲师。科里博士拥有以患者为导向的研究、胃肠病学和肝病学背景。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肝（NAFLD）之间的相互作用。她在这些领域的工作已发表 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子之一，这表明OSA可能在NAFLD发展中发挥作用。 OSA 和 NAFLD 都是重要的公共卫生状况。 NAFLD 影响 30% 的美国人，并可导致肝硬化和肝细胞癌。据估计，超过 1200 万美国人患有 OSA，这种疾病会恶化代谢疾病，并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带来新的治疗选择并改善公共卫生结果。利用从这些研究中获得的知识，科里博士的提议将侧重于检验三个假设： 1) OSA 与 NAFLD 患病率增加有关，2) OSA 和 NAFLD 之间的相互作用是通过 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。虽然动物研究发现慢性间歇性缺氧（OSA 的实验模拟）与 NAFLD 之间存在密切关系，但人类研究受到方法学问题的限制，导致结果不确定。为了完成这项提案，科里博士将需要在研究设计、统计分析和阻塞性睡眠呼吸暂停力学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 博士是一位著名的肝病学基础和临床研究者，Atul Malhotra 博士是一位 OSA 研究领域的资深医师科学家。两位博士。 Chung 和 Malhotra 在指导临床研究人员方面建立了良好的记录，并都获得了 NIH K24 奖。 Corey 博士还将接受代谢研究领域知名研究者、K24 接受者 Steven Grinspoon 博士和经验丰富的生物统计学家兼导师 Shiva Gautam 博士的指导。她将接受哈佛医学院医学硕士项目的研究设计、高级生物统计学和预测建模方面的正式教学培训。她还将通过哈佛-麻省理工学院健康科学与技术课程接受 OSA 病理生理学培训，由她的共同导师 Malhotra 博士领导。有了这些额外的教育和指导，以及 MGH 提供的支持环境，Corey 博士将做好准备完成这项提案并发展成为一名独立的临床研究者。