The Growth Hormone and Insulin-like Growth Factor-1 Axis in Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis

项目摘要 非酒精性脂肪性肝病(NAFLD)是一种高度流行的肝病，目前约有 80%的肥胖者。导致肝脏脂肪发育和向非酒精性进展的因素 脂肪性肝炎(NASH)，包括炎症和纤维化，人们知之甚少，而且有明显的未满足 鉴于缺乏有效的治疗方法，需要在这一领域进行研究。这项拟议的研究具有重要意义，因为 它有可能阐明这种高度流行的公众的模糊的病理生理机制。 健康疾病，并确定新的治疗目标 该项目的科学目标是阐明生长激素(GH)和胰岛素样生长的作用。 胰岛素样生长因子-1(IGF-1)在NAFLD和NASH病理生理学中的作用中心假设是相对生长激素 肥胖和IGF-1缺乏与NAFLD和NASH的发生和发展有关，以及 服用生长激素将减少脂肪变性、炎症和纤维化。目标1将决定这一关系 GH/IGF-1轴与肝内脂肪含量、炎症和纤维化之间的关系。AIM 2调查了 小剂量生长激素与安慰剂对活检证实的NASH患者这些终点的影响。这项提议的理由是 肥胖中相对的GH/IGF-1缺乏可能在NAFLD的发生发展中起作用 NASH具有消脂、抗炎和抗纤维化的特性，并基于我们的初步数据。 这位候选人是哈佛医学院的医学讲师，也是 马萨诸塞州综合医院(MGH)，非常有资格并坚定地致力于开发 独立调查员的职业生涯。她的短期目标是发展技能并获得初步的 向她的第一个R级独立NIH资助研究过渡所需的数据。她长长的- 学期目标是成为一名独立的、以患者为导向的内分泌机制研究人员， 有助于NAFLD的病因和进展为NASH。她得到了一位专家的支持，而且非常- 由成功的、NIH支持的临床研究人员组成的投资导师团队 神经内分泌学、肝脏病学和放射学，拥有令人印象深刻的成功记录，包括 奖励、试点赠款和出版物。她和她的导师设计了一个有针对性的培训计划，包括 共同指导和说教项目。 麻省理工学院和哈佛医学院的制度环境很好，拥有多种资源 可从MGH医学部、MGH临床研究部和哈佛大学 医学院临床转化科学中心拨款，所有这些都提供了无数的教学机会， 为候选人提供设施和支持。神经内分泌科和医学部已经做出了 对候选人的坚定承诺，包括90%受保护的时间、空间、研究协调员支持和 教师任命，目标是促进候选人作为独立调查员的职业生涯。

PROJECT ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent form of liver disease present in approximately 80% of obese individuals. The factors leading to the development of liver fat and progression to nonalcoholic steatohepatitis (NASH), including inflammation and fibrosis, are poorly understood, and there is a clear unmet research need in this area given the lack of effective therapies. The proposed research is significant because it has the potential to elucidate poorly defined pathophysiologic mechanisms of this highly prevalent public health disease, and identify new therapeutic targets The scientific goal of this project is to elucidate the role of the growth hormone (GH) and insulin-like growth factor-1 (IGF-1) axis in the pathophysiology of NAFLD and NASH. The central hypothesis is that relative GH and IGF-1 deficiency in obesity are associated with development and progression of NAFLD and NASH, and that GH administration will reduce steatosis, inflammation and fibrosis. Aim 1 will determine the relationship between the GH/IGF-1 axis and intrahepatic lipid content, inflammation and fibrosis. Aim 2 investigates the effect of low-dose GH vs. placebo on these endpoints in biopsy-proven NASH. The rationale for this proposal is that relative GH/IGF-1 deficiency in obesity may play a role in the development and progression of NAFLD and NASH given its lipolytic, anti-inflammatory and anti-fibrotic properties and based on our preliminary data. The candidate is an Instructor of Medicine at Harvard Medical School and Assistant in Medicine at Massachusetts General Hospital (MGH) who is highly qualified for and deeply committed to developing a career as an independent investigator. Her short-term goal is to develop the skills and obtain the preliminary data necessary to make the transition to her first R-level independent NIH grant-supported research. Her long- term goal is to become an independent, patient-oriented researcher in endocrine mechanisms that may contribute to the etiopathology of NAFLD and progression to NASH. She is supported by an expert and highly- invested mentorship team composed of successful, NIH-supported clinical investigators in Neuroendocrinology, Hepatology and Radiology and has an impressive track record of success, including awards, pilot grants and publications. She and her mentors have designed a targeted training plan consisting of co-mentorship and a didactic program. The institutional environment is outstanding at MGH and Harvard Medical School, with multiple resources available from the MGH Department of Medicine, the MGH Division of Clinical Research, and the Harvard Medical School Clinical Translational Science Center grant, all of which offer a myriad of didactic opportunities, facilities and support to the candidate. The Neuroendocrine Unit and Department of Medicine have made a strong commitment to the candidate, including 90% protected time, space, study coordinator support and a faculty appointment, with the goal of fostering the candidate's career as an independent investigator.