Non Alcoholic Steatohepatitis Clinical Research Network

摘要 本申请是为了继续克利夫兰诊所临床研究中心及其非酒精的子研究中心， 脂肪性肝炎临床研究网络（NASH CRN）。非酒精性脂肪肝（NAFLD）几乎 北美三分之一的成年人和五分之一的儿童，是美国的一个主要公共卫生问题。 NAFLD和更严重的形式非酒精性脂肪性肝炎（NASH）导致肝硬化和原发性肝硬化。 癌症以及与肝脏、心血管和癌症有关的发病率和死亡率， 医疗负担和成本。NASH CRN是理想的和独特的定位，以影响持续的 NASH的公共卫生负担，只能通过这个大型研究联盟来解决， 在以前的周期中表现出成功的跟踪记录。NASH CRN的主要目标是执行 关于成人和儿童NASH和NAFLD的高质量、可重复的临床研究， 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、治疗和临床管理。在NASH CRN的这个资助周期中，成人和儿童 在前一个供资周期启动的治疗试验将完成，新的治疗试验， 包括2a期机制证明和2b期临床试验，将启动以证据为基础的 安全、有效和廉价的治疗选择。具体来说，我们建议将维生素D3 通过提出一项网络范围内的研究，比较每日5000 IU至1000 IU的胆钙化醇作为NASH的治疗 24个月NAFLD成人和儿童的纵向队列将得到扩展， 前瞻性地定义疾病的自然史、心血管和代谢危险因素， 生物标志物的发现和验证，以及非侵入性技术的开发和验证， 评估和识别NASH/NAFLD患者，干预措施的应答者，并确定疾病发生率 进展我们将纳入正在接受减肥手术评估的患者。最后， 我们将使用反向翻译的方法来开发新的生物标志物，并确定潜在的治疗方法， NASH中的目标。具体来说，我们将评估一种新的高密度胆固醇功能测定法和一种新的高密度胆固醇功能测定法。 使用来自先前资助周期的生物储存库样本和资源的NAFLD microRNA签名 以补充目前为此目的进行的研究。克利夫兰研究中心在临床和 NASH CRN自成立以来的转化研究成功。我们一直是领先的招生网站， PIVENS和FLINT成人试验以及TONIC和CynCh儿童试验。克利夫兰研究中心的研究人员 在提高对全身异常（包括心血管和 NAFLD中的代谢紊乱。鉴于我们网站的高招聘、保留和数据质量， 我们继续致力于合作的成功，NASH CRN准备继续其主要活动 对该领域的影响，并推进NIH改善公众健康的使命。

ABSTRACT This application is for the continuation of the Cleveland Clinic clinical site and its subsites of the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). Nonalcoholic fatty liver disease (NAFLD) affects nearly a third of adults and a fifth of children in North America and is a major public health issue in the United States. NAFLD, and the more severe form, nonalcoholic steatohepatitis (NASH), lead to cirrhosis and primary liver cancer, as well as liver-, cardiovascular-, and cancer-related morbidity and mortality, resulting in major increases in health care burdens and costs. The NASH CRN is ideally and uniquely positioned to impact the continuing public health burden of NASH that can only be addressed through this large research consortium with a demonstrated track record of success in previous cycles. The primary objective of the NASH CRN is to perform high quality, reproducible clinical research on NASH and NAFLD in adults and children focusing on the pathogenesis that will provide the basis for understanding the natural history and developing means of better diagnosis, treatment, and clinical management. In this funding cycle of the NASH CRN, the adult and pediatric therapeutic trials initiated during the previous funding cycle 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, and inexpensive. Specifically, we propose to repurpose vitamin D3 (cholecalciferol) as a treatment for NASH by proposing a network wide study comparing 5000 IU to 1000 IU daily for 24 months. The longitudinal cohort of adults and children with NAFLD will be extended, which will prospectively define the natural history of the disease, the cardiovascular and metabolic risk factors, and will aid in biomarker discovery and validation, and the development and validation of non-invasive techniques to evaluate and identify patients with NASH/NAFLD, responders to interventions and determine the rate of disease progression. We will include patients being evaluated for and undergoing bariatric surgery to this cohort. Finally, we will use a reverse translational approach to develop novel biomarkers and identify potential therapeutic targets in NASH. Specifically, we will evaluate a novel functional assay for high density cholesterol and a microRNA signature for NAFLD using the biorepository samples and resources from the previous funding cycles to complement the current studies for this aim. The Cleveland site has played a key role in both the clinical and translational research success of the NASH CRN since its inception. We have been a leading enrolling site in the PIVENS and FLINT trials in adults and TONIC and CynCh trials in children. The Cleveland site investigators are uniquely placed in improving the understanding of systemic abnormalities including cardiovascular and metabolic perturbations in NAFLD. Given the high recruitment, retention and quality of data from our site and our continued commitment to the success of the collaboration, the NASH CRN is poised to continue its major impact on the field and advance the mission of the NIH to improve the health of the public.