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Tesamorelin Effects on Liver Fat and Histology in HIV: A Collaborative U01 Grant

Tesamorelin 对 HIV 肝脏脂肪和组织学的影响：U01 合作资助

基本信息

批准号：
9177746
负责人：
STEVEN K. GRINSPOON
金额：
$ 68.53万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-15 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9177746
关键词：
Acquired Immunodeficiency Syndrome Address Adipose tissue Adult Adverse effects Applications Grants Biopsy Cardiovascular Diseases Central obesity Chronic Cirrhosis Clinical Collaborations Comorbidity Data Development Dyslipidemias Enzymes FDA approved Fasting Fatty Liver Fatty acid glycerol esters Fibrosis General Hospitals General Population Genes Grant HIV HIV Infections Health Hepatic Hepatocellular Damage Hepatocyte High Prevalence Histologic Histology Hormonal Individual Inflammation Inflammatory Injury Insulin Resistance Intervention Investigation Lead Liver Liver Fibrosis Liver diseases Magnetic Resonance Spectroscopy Massachusetts Measures Medicine Metabolic National Institute of Allergy and Infectious Disease Obesity Participant Pathologist Patients Peripheral Phase Phenotype Physiological Physiology Placebos Play Population Process Randomized Controlled Trials Recruitment Activity Research Research Methodology Research Personnel Role Somatotropin Somatotropin-Releasing Hormone Steatohepatitis Testing Therapeutic Transaminases Triglycerides United States National Institutes of Health Visceral Vitamin E Work adiponectin antiretroviral therapy cohort design elastography experience glucose metabolism hepatic gluconeogenesis hormone analog improved indexing insight insulin sensitivity lipid biosynthesis lipid metabolism liver biopsy liver imaging liver inflammation liver injury mortality non-alcoholic fatty liver nonalcoholic steatohepatitis novel novel strategies novel therapeutics open label professor public health relevance stable isotope treatment strategy

项目摘要

DESCRIPTION (provided by applicant): This project proposes a collaboration between Dr. Colleen Hadigan, Intramural Investigator at NIAID, and Dr. Steven Grinspoon, Professor of Medicine at MGH, to assess a novel strategy to reduce liver fat and improve liver histology in the large number of HIV patients with NAFLD and NASH. Liver disease is one of the most significant chronic co-morbid conditions among HIV patients, and, in the era of antiretroviral therapy, mortality from liver disease is second only to AIDS related mortality. An increasing percentage of HIV-infected patients (30-40%) are thought to have non-alcoholic fatty liver disease (NAFLD), characterized by triglyceride accumulation in hepatocytes that may progress to hepatic inflammation and significant hepatocellular injury. To date, therapies to treat NAFLD in HIV have been poorly studied. Investigation of new therapies is particularly urgent in HIV, in which contributors to NAFLD may be distinct from those in the general population. The current application will investigate a novel strategy to treat NAFLD in HIV using tesamorelin, a growth hormone releasing hormone (GHRH) analogue, which will address two potentially critical contributors to liver fat in HIV, namely increased visceral adiposity and increased hepatic de novo lipogenesis. Growth hormone is generally decreased in HIV-infected individuals with increased visceral adiposity. Tesamorelin, which increases endogenous growth hormone secretion, is an FDA approved therapy to reduce visceral fat in this population. Our current application builds on strong preliminary data, showing that tesamorelin reduced liver fat by 40% in association with reductions in visceral fat in a cohort chosen for visceral obesity. In the proposed studies, we will assess the efficacy of tesamorelin to reduce liver fat in patients chosen for NAFLD and increased transaminases, with the latter indicating inflammation and/or hepatocellular damage. We will also investigate effects of GHRH analogue on liver inflammation, hepatocellular damage, and liver fibrosis. We hypothesize that tesamorelin will reduce liver fat and also reduce hepatic inflammation and potentially hepatocellular injury. Further, to elucidate metabolic correlates of NAFLD, we will assess the effects of tesamorelin on hepatic de novo lipogenesis, and the effects of liver fat reduction on hepatic and whole body insulin sensitivity. In this U01 grant application, we will leverage a strong collaboration between experts in HIV-associated liver disease at NIAID, including Drs. Colleen Hadigan and Caryn Morse and David Kleiner, with a well-characterized clinical cohort with NAFLD and significant expertise in liver histology and Dr. Grinspoon and his team at MGH, who have worked to develop a successful strategy to reduce VAT in HIV patients. This application builds on preliminary data from both groups demonstrating the linkage between NAFLD and liver inflammation in HIV and the robust and novel effects of tesamorelin to reduce hepatic fat in this population. The proposed investigation will provide insight into the mechanism of this process in HIV patients and may suggest the first successful treatment for hepatic steatosis and inflammation in HIV patients.

描述（由申请人提供）：本项目提议由NIAID的校内研究员Colleen Hadigan博士和MGH的医学教授Steven Grinspoon博士合作，评估一种新的策略来减少大量NAFLD和NASH的HIV患者的肝脏脂肪和改善肝脏组织学。肝病是艾滋病毒患者中最重要的慢性合并症之一，在抗逆转录病毒治疗时代，肝病的死亡率仅次于艾滋病相关死亡率。越来越多的hiv感染患者（30-40%）被认为患有非酒精性脂肪性肝病（NAFLD），其特征是肝细胞中甘油三酯积聚，可能发展为肝脏炎症和严重的肝细胞损伤。迄今为止，治疗HIV NAFLD的疗法研究甚少。研究新的治疗方法在HIV中尤为迫切，因为导致NAFLD的因素可能与一般人群不同。目前的申请将研究使用tesamorelin治疗HIV NAFLD的新策略，tesamorelin是一种生长激素释放激素（GHRH）类似物，它将解决HIV中肝脏脂肪的两个潜在关键因素，即内脏脂肪增加和肝脏新生脂肪增加。生长激素在感染hiv的个体中普遍降低，并伴有内脏脂肪增加。替沙莫瑞林，增加内源性生长激素分泌，是FDA批准的治疗减少内脏脂肪的人群。我们目前的应用建立在强有力的初步数据基础上，表明替沙莫林在内脏肥胖的队列中减少了40%的肝脏脂肪和内脏脂肪的减少。在拟议的研究中，我们将评估替沙莫瑞林在NAFLD和转氨酶升高（后者表明炎症和/或肝细胞损伤）患者中降低肝脏脂肪的疗效。我们还将研究GHRH类似物对肝脏炎症、肝细胞损伤和肝纤维化的影响。我们假设替沙莫林可以减少肝脏脂肪，也可以减少肝脏炎症和潜在的肝细胞损伤。此外，为了阐明NAFLD的代谢相关因素，我们将评估替沙莫林对肝脏新生脂肪生成的影响，以及肝脏脂肪减少对肝脏和全身胰岛素敏感性的影响。在这次U01资助申请中，我们将利用与