Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN)

项目摘要 非酒精性脂肪性肝病(NAFLD)和非酒精性脂肪性肝炎(NASH)是最常见的 美国慢性肝病的重要原因，每3个成年人中有1个，每5个儿童中有1个 受影响。NAFLD，尤其是NASH，与肝脏、心血管和癌症相关的增加有关 死亡率。NASH临床研究网络(NASH CRN)成立于2002年，旨在进行研究 与儿童和成人的临床特点、危险因素、发病机制、自然病史和治疗有关。 在上一个资金周期中，CRN积累了一个全面的数据库，其中包括来自5个国家的4,544名患者 在本资助期内(至18日10月1日)进行的研究。完成了两项临床试验(Flint和CyNCH) 用于儿童NAFLD的氯沙坦(STOP-NAFLD)试验正在进行中，第一名患者将于10月随机入选 2018年。此外，NASH CRN已存档总计504,685个生物样本(血清、血浆、肝组织、 DNA和c DNA)，并提取了28,436个样本进行翻译 使用辅助研究机制进行研究。自2004年以来，共有31份出版物是由 104项获批准的附属研究。在上一个资金周期取得成功的基础上，NIDDK发布了RFA- DK-08-505，目标是将NASH CRN再延续5年。该计划的目标 NASH CRN在下一个资助期是： (A)完成在上一个供资期间启动的全网研究。这是两个观察性的 纵向队列研究(成人和儿童NAFLD数据库2研究)和随机双盲 氯沙坦治疗儿童非酒精性脂肪肝对照试验(Stop-CO，n=110)。NAFLD数据库可以是 为实现下一个供资期间的额外成果目标而进行了修订。这些修改可能包括 延长那些登记的人的随访时间，考虑在以下几个子集进行后续肝活检 患者，并扩大到更多地关注心血管、糖尿病和癌症相关的结果； (B)根据临床材料和存档的生物标本进行新的翻译研究 以前的资助期包括自噬的新标记物，自噬是控制细胞脂质的重要手段 相对于肝脏中的其他脂质调节途径和在NAFLD疾病中的潜在作用，这一点还没有得到充分的研究 严重性；以及 (C)为患有非酒精性鼻炎的成人和儿童进行额外的新颖治疗研究，例如建议的 氨氯地平作为促进自噬疗法在患有NASH的儿童和成人中的第二阶段研究(Ampat试验)。 辅助研究将利用新的合作(例如免疫学、微生物组)来开发全面的 NAFLD/NASH模式，将允许识别处于危险中的成年人和儿童，并建立有效的 NASH的预防和治疗策略。

Project Summary Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) ranks as one of the most important causes of chronic liver disease in the United States, with 1 of every 3 adults and 1 of every 5 children affected. NAFLD, especially NASH, is associated with increased liver, cardiovascular and cancer-related mortality. The NASH Clinical Research Network (NASH CRN) was established in 2002 to conduct research related to its clinical features, risk factors, pathogenesis, natural history and treatment in children and adults. Over the last funding cycle, the CRN has accrued a comprehensive database of 4,544 patients from five studies during the current funding period (to 1 Oct 18). Two clinical trials were completed (FLINT and CyNCh) and The Losartan for Pediatric NAFLD (STOP-NAFLD) trial is underway with first patient randomized in Oct 2018. Additionally, the NASH CRN has archived a total of 504,685 biospecimens (serum, plasma, liver tissue, DNA ad cDNA) in the NIDDK Biorepository, and 28,436 samples have been withdrawn for translational research using the Ancillary Studies mechanism. Since 2004, a total of 31 publications have resulted from the 104 approved Ancillary Studies. Building on the success of the last funding cycle, the NIDDK has issued RFA- DK-08-505 with the objectives of continue the NASH CRN for an additional 5 years. The objectives of the NASH CRN during this next funding period are: (a) to complete the network-wide studies initiated during the last funding period. These are two observational longitudinal cohort studies (the Adult and Pediatric NAFLD Database 2 studies) and a randomized double blind controlled therapeutic trial of losartan for NAFLD in children (STOP-CO, n=110). The NAFLD database may be amended to meet additional outcome goals during the next funding period. These modifications may include extending the length of follow-up of those enrolled, consideration of a follow-up liver biopsy in a subset of patients, and expansion to include greater focus on cardiovascular, diabetes and cancer-related outcomes; (b) to conduct new translational studies based on the clinical material and archived biospecimens from previous funding periods including novel markers of autophagy, an important means of controlling cellular lipids that is understudied relative to other lipid-regulating pathways in the liver and potential role in NAFLD disease severity; and (c) to conduct additional novel therapeutic studies in adults and children with NASH, such as the proposed phase 2 study of amlodipine, as pro-autophagic therapy, in children and adults with NASH (AMPAT Trial). Ancillary studies will leverage new collaborations (e.g. immunology, microbiome) to develop a comprehensive model of NAFLD/NASH which will allow identification of adults and children at risk and establish effective preventive and treatment strategies against NASH.