The Saint Louis University Component of the NASH CRN

摘要 该应用程序是非酒精性脂肪性肝炎临床研究网络（NASH）的延续 CRN）临床中心在圣刘易斯大学和其儿科组成部分在贝勒大学。纳什 临床研究网络（NASH CRN）自2002年以来一直由NIDDK赞助，并于2009年更新 和2014年。非酒精性脂肪肝（NAFLD）影响超过三分之一的成年人和三分之一的成年人。 5名儿童美国NAFLD，尤其是其最严重的非酒精性脂肪性肝炎（NASH），可能 导致肝硬化和原发性肝癌，从而导致死亡或肝移植和巨大健康负担 和成本。NASH CRN是理想的和独特的定位，以影响日益增长的公共卫生意义 这只能通过大型研究联盟来解决。NASH CRN的主要目的 在成人和儿童中进行NASH和NAFLD治疗药物的临床试验。一个紧密联系的 高优先级的次要目标是在NASH和NAFLD中进行转化研究，重点是 发病机制，这将提供基础，了解自然史和发展手段，更好地 诊断、预防、治疗和临床管理。在NASH CRN的下一阶段，成人和 在前一个资助周期启动的儿科治疗试验将完成， 将启动试验，包括2a期机制证明和2b期临床试验，以开发证据- 这些治疗方案是安全、有效、简单、具有成本效益和广泛适用的。纵向 在过去十年中收集的NAFLD成人和儿童队列将前瞻性地扩展到 定义疾病的自然史，心血管和代谢风险因素，并将有助于生物标志物 发现和验证。该队列还将促进非侵入性的开发和验证。 识别NASH患者的技术，预测谁将对治疗作出反应，并识别影响NASH的因素。 疾病进展。本申请中提出的治疗试验是膳食补充剂的2a期试验， 叫三丁酸甘油酯三丁酸甘油酯约占黄油的3%，是丁酸的前药。丁酸是一种 胃肠道细菌在正常代谢膳食纤维过程中产生的重要代谢产物。 丁酸已被证明是结肠细胞层的主要能量来源， 促进这些细胞的功能，防止有害细菌产物进入血液， 损害肝脏。它还被发现对整个身体的新陈代谢有有益的影响。 动物数据支持研究丁酸或其前体三丁酸甘油酯治疗NASH的基本原理， 人类的数据非常有限。在本申请中提出了另外的转化研究，以从机理上 了解三丁酸甘油酯治疗肠道通透性和全身代谢的益处。NASH CRN是 准备继续其对该领域的重大影响，并直接推进美国国立卫生研究院的使命。 卫生，提高公众的健康水平。

Abstract This application is for the Continuation of the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) clinical center at Saint Louis University and its pediatric component at Baylor University. The NASH Clinical Research Network (NASH CRN) has been sponsored by the NIDDK since 2002 with renewals in 2009 and 2014. Nonalcoholic fatty liver disease (NAFLD) affects more than one out of three adults and one out of five children the U.S. NAFLD, and especially its most severe subset nonalcoholic steatohepatitis (NASH), may lead to cirrhosis and primary liver cancer resulting in death or liver transplant and substantial health burdens and costs. The NASH CRN is ideally and uniquely positioned to impact the growing public health significance of NASH that can only be addressed via a large research consortium. The primary objective of the NASH CRN is to perform clinical trials of therapeutic agents for NASH and NAFLD in adults and children. A closely linked and high priority secondary objective is to conduct translational research in NASH and NAFLD focusing on the pathogenesis that will provide the basis for understanding the natural history and developing means of better diagnosis, prevention, treatment, and clinical management. In the next phase of the NASH CRN, the adult and pediatric therapeutic trials initiated during the previous funding cycles will be completed and new therapeutic trials, including phase 2a proof of mechanism and phase 2b clinical trials will be initiated to develop evidence- based treatment options that are safe, effective, simple, cost-effective and broadly applicable. The longitudinal cohort of adults and children with NAFLD collected over the past decade will be extended to prospectively define the natural history of the disease, the cardiovascular and metabolic risk factors, and will aid in biomarker discovery and validation. This cohort will also facilitate the development and validation of non-invasive techniques to identify those with NASH, predict who will respond to treatments, and identify factors affecting disease progression. The treatment trial proposed in this application is a phase 2a trial of a dietary supplement called tributyrin. Tributyrin makes up about 3% of butter and is a prodrug of butyric acid. Butyric acid is an important metabolite produced by bacteria in the GI tract during their normal metabolism of dietary fiber. Butyric acid has been shown to be the primary energy source for the layer of cells that line the colon where it promotes the function of these cells and prevents harmful bacterial products from entering the blood and damaging the liver. It has also been found to have beneficial effects on metabolism throughout the body. Animal data supports the rationale for studying butyric acid, or its precursor tributyrin, in treating NASH but human data are very limited. Additional translational studies are proposed in this application to mechanistically understand the benefits of tributyrin treatment gut permeability and whole-body metabolism. The NASH CRN is poised to continue its major impact on the field and directly advance the mission of the National Institutes of Health to improve the health of the public.