Clinical Research Network in NASH

NASH 临床研究网络

• 批准号: 6480202
• 负责人: NATHAN M BASS
• 金额: $ 31.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-15 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6480202
• 关键词: clinical research; cooperative study; epidemiology; fatty liver; genetic susceptibility; hepatitis; human subject; lipid metabolism; longitudinal human study; pathologic process; patient /disease registry; patient oriented research; peroxisome proliferator activated receptor; questionnaires; tissue resource /registry; transaminases

Non-alcoholic fatty liver disease (NAFLD) is a common cause of asymptomatic liver test abnormalities in the general population often associated with obesity and insulin resistance. The severe public health problem with a significant impact in terms of morbidity, mortality and health care cost outcomes. This proposal brings together a unique consortium of investigators and resources within the State of California with a plan for participating Clinical Center in the NASH Clinical Research Network. The proposed NASH patient informational database and tissue bank will comprise cross-sectional and prospective cohorts derived from four separate sources, each providing distinct epidemiological facets and research potential. These include tertiary care referral specialty clinics at two large university medical centers and an HMO patient population. We propose to identify patients with definite (biopsy-proven) NASH and probable (association-defined) NAFLD/NASH from these sources, and outline a plan for longitudinal follow-up of selected sub-populations for the purpose of studying the natural history of progression, identification of risk factors for progression and to enable the implementation of therapeutic trials in patients with NASH. Secondly, we describe two research protocols that would use the NASH Clinical Research Network database and tissue bank to test the hypothesis, supported by our preliminary data that familial/genetic factors underlie the development of NASH and its progression. These projects include: 1) Determining genetic factors predisposing to NASH by exploring a possible etiologic relationship between our newly discovered genomic variants and lipid metabolism in patients (and their kindreds) with NASH. These involve key regulatory components of cellular lipid metabolism (peroxisome proliferator- activated receptors and microsomal triglyceride transfer protein and would be prime candidate genes for exploration utilizing the Network resources; and 2) To design and validate a questionnaire to identify factors in the family history that are predictors of the presence of NASH in patients with unexplained chronically elevated aminotransferases and that are independent predictors of disease severity and progression. We plan to use this approach to identify kindreds to correlate familial factors with specific mutations in key regulatory genes of lipid metabolism in order to elucidate the genetic basis for NASH and the putative genetic association between NASH and cryptogenic cirrhosis.

非酒精性脂肪性肝病(NAFLD)是普通人群中无症状肝功能异常的常见原因，通常与肥胖和胰岛素抵抗有关。严重的公共卫生问题对发病率、死亡率和医疗费用结果产生重大影响。这项提案将加利福尼亚州内一个独特的研究人员和资源联盟与一个参与NASH临床研究网络的临床中心计划结合在一起。拟议的NASH患者信息数据库和组织库将包括来自四个不同来源的横断面和预期队列，每个来源都提供不同的流行病学方面和研究潜力。其中包括两个大型大学医疗中心的三级护理转诊专科诊所和HMO患者群体。我们建议从这些来源中确定确诊的(活检证实的)NASH患者和可能的(关联定义的)NAFLD/NASH患者，并勾勒出对选定的亚群进行纵向随访的计划，目的是研究进展的自然历史，识别进展的危险因素，并使NASH患者能够实施治疗试验。其次，我们描述了两个研究方案，这两个方案将使用NASH临床研究网络数据库和组织库来验证这一假设，这两个方案得到了我们的初步数据的支持，即家族/遗传因素是NASH发生和发展的基础。这些项目包括：1)通过探索我们新发现的基因组变异与NASH患者(及其亲属)脂代谢之间的可能病因学关系，确定NASH的易感遗传因素。这些涉及细胞脂代谢的关键调节成分(过氧化物体增殖物激活受体和微粒体甘油三酯转移蛋白)，将是利用网络资源进行探索的首选候选基因；以及2)设计和验证问卷，以确定家族史中的因素，这些因素是原因不明的慢性转氨酶升高患者中NASH的存在的预测因素，并且是疾病严重程度和进展的独立预测因素。我们计划使用这种方法来确定家族因素与脂代谢关键调控基因的特定突变之间的关联，以阐明NASH的遗传基础以及NASH和隐源性肝硬变之间可能的遗传关联。