Clinical Research Network in NASH

NASH 临床研究网络

• 批准号: 6863730
• 负责人: NATHAN M BASS
• 金额: $ 47.25万
• 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 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6863730
• 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）是普通人群无症状肝检查异常的常见原因，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、死亡率和保健费用结果产生重大影响。该提案汇集了加州独特的研究人员和资源联盟，并计划参与NASH临床研究网络的临床中心。拟议的NASH患者信息数据库和组织库将包括来自四个独立来源的横断面和前瞻性队列，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保健转诊专科诊所和HMO患者群体。我们建议从这些来源中确定明确的（活检证实的）NASH患者和可能的（关联定义的）NAFLD/NASH患者，并概述一项计划，对选定的亚群进行纵向随访，以研究进展的自然史，确定进展的危险因素，并使NASH患者能够实施治疗试验。其次，我们描述了两种研究方案，它们将使用NASH临床研究网络数据库和组织库来验证我们的假设，我们的初步数据支持家族/遗传因素是NASH发展及其进展的基础。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）脂质代谢之间可能的病因学关系，确定易患NASH的遗传因素。这些涉及细胞脂质代谢的关键调控成分（过氧化物酶体增殖物激活受体和微粒体甘油三酯转移蛋白），将是利用网络资源探索的主要候选基因；2)设计并验证一份问卷，以确定家族史中预测不明原因的慢性转氨酶升高患者是否存在NASH的因素，以及这些因素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质代谢关键调控基因特异性突变的相关性，以阐明NASH的遗传基础以及NASH与隐源性肝硬化之间的假定遗传关联。