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

非酒精性脂肪肝和非酒精性脂肪性肝炎中的生长激素和胰岛素样生长因子-1 轴

• 批准号: 10200965
• 负责人: Laura Elisabeth Dichtel
• 金额: $ 5.4万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-15 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200965
• 关键词: Adipose tissue; Age; Alcohol consumption; Animal Model; Anti-Inflammatory Agents; Appointment; Area; Award; Biopsy; Center for Translational Science Activities; Cirrhosis; Clinic; Clinical; Clinical Data; Clinical Investigator; Clinical Research; Complication; Data; Deposition; Development; Disease; Disease Progression; Dose; Endocrine; Endocrinology; Environment; Enzymes; FDA approved; Faculty; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Fostering; Functional disorder; General Hospitals; Goals; Grant; Growth Hormone Receptor; Hepatic; Hepatocyte; Hepatology; High Prevalence; Histologic; Hormone replacement therapy; Hospital Departments; Hypopituitarism; Imaging Techniques; Individual; Infiltration; Inflammation; Inflammatory; Insulin Resistance; Insulin-Like Growth Factor I; Knock-out; Lipids; Liver; Liver Fibrosis; Liver diseases; Lobular; Magnetic Resonance Spectroscopy; Massachusetts; Measures; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Neuroendocrinology; Neurosecretory Systems; Obesity; Overweight; Oxidative Stress; Pathogenesis; Patients; Phenotype; Physiological; Pituitary Gland; Placebos; Play; Process; Production; Property; Protons; Public Health; Publications; Radiology Specialty; Research; Research Personnel; Research Support; Resources; Role; Scientist; Serum Markers; Severities; Signal Pathway; Somatotropin; Time; Training; United States National Institutes of Health; Visceral; base; career; cohort; design; effective therapy; fibrogenesis; growth hormone deficiency; hormonal signals; human tissue; inflammatory marker; instructor; intrahepatic; liver development; liver inflammation; liver transplantation; medical schools; metabolic imaging; multidisciplinary; new therapeutic target; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel imaging technique; patient oriented; pre-clinical; prevent; primary endpoint; programs; radiologist; reconstitution; secondary endpoint; skills; success

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.

项目摘要 非酒精性脂肪性肝病（NAFLD）是一种高度流行的肝病形式， 80%的肥胖者。导致肝脏脂肪发展和进展为非酒精性的因素 脂肪性肝炎（NASH），包括炎症和纤维化，知之甚少， 由于缺乏有效的治疗方法，这方面的研究需要。这项研究意义重大，因为 它有可能阐明这一高度流行的公众不明确的病理生理机制， 健康疾病，并确定新的治疗靶点 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 因子-1（IGF-1）轴在NAFLD和NASH的病理生理学中的作用。核心假设是相对生长激素 肥胖症中IGF-1缺乏与NAFLD和NASH的发生和进展相关， GH给药将减少脂肪变性、炎症和纤维化。目标1将决定关系 GH/IGF-1轴与肝内脂质含量、炎症和纤维化之间的关系。目标2调查了 在经活检证实的NASH中，低剂量GH与安慰剂相比对这些终点的影响。这项建议的理由是， 肥胖者相对GH/IGF-1缺乏可能在NAFLD的发生和发展中起作用 和NASH，考虑到其脂解、抗炎和抗纤维化特性并基于我们的初步数据。 候选人是哈佛医学院的医学讲师和 马萨诸塞州总医院（MGH）是一家高素质的医院，致力于开发 作为一名独立调查员。她的短期目标是发展技能并获得初步的 必要的数据，使过渡到她的第一个R级独立NIH资助的研究。她的长- 长期目标是成为一个独立的，以病人为导向的内分泌机制研究人员， 有助于NAFLD的发病机制和向NASH的进展。她得到了一位专家的支持，并高度- 由成功的，NIH支持的临床研究者组成的投资指导团队， 神经内分泌学、肝脏病学和放射学，并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， 共同指导和教学计划。 MGH和哈佛医学院的制度环境非常出色，拥有多种资源 可从MGH医学系、MGH临床研究部和哈佛大学获得 医学院临床转化科学中心赠款，所有这些都提供了无数的教学机会， 为候选人提供便利和支持。神经内分泌科和内科已经做了一个 对候选人的坚定承诺，包括90%的保护时间，空间，研究协调员的支持和 教师任命，以促进候选人的职业生涯作为一个独立的调查员的目标。