LIPIDOMICS BASED DIAGNOSTICS FOR NONALCOHOLIC STEATOHEPATITIS

 描述(申请人提供)：非酒精性脂肪性肝炎(NASH)是一种侵袭性的非酒精性脂肪性肝病(NAFLD)，影响3%-4%的成年人，并在15%-20%的受试者中进展为肝硬变。目前NASH还没有得到批准的治疗方法，唯一准确诊断这种情况的方法是肝脏活检，这是有创的，痛苦的，有时还会与死亡有关。许多人认为，缺乏诊断NASH的“即时”诊断工具、评估疾病进展与退化以及对各种疗法的反应，是大规模识别受影响个体和开发针对NASH的药物的最重要障碍。这项建议代表了多PI努力，以开发基于脂质组学的生物标记物小组，以填补这些知识空白。来自NIDDK NASH临床研究网络(CRN)的Sanyal博士(Pi)将领导这项工作，而之前领导NIGMS Liped_MAPS联盟的Dennis博士(Co-Pi)将领导脂质分析。NASH CRN数据协调中心(DCC)将继续担任该提案的DCC。这些研究将从Nash CRN生物储存库中提取，该储存库包含2000多名高度表型的NAFLD患者在肝脏活检时提取的血浆。三个特定的目标将检验这一假设，即NAFLD中脂代谢的变化可以识别循环脂信号，以诊断NASH、疾病进展和对特定治疗的反应。目标1将定义并验证对潜在NASH及其严重性的循环血脂谱诊断。将研究一个模型构建队列和两个验证队列。模型构建队列将包括患有和不患有NAFLD的受试者。验证队列将包括：(1)一组NAFLD表型各不相同的受试者，以及年龄、性别、种族和体重匹配的对照组，没有NAFLD，以及(2)一组预期的受试者，他们将接受临床指示的NASH肝脏活检。目标2将定义诊断NASH疾病进展的循环血脂的变化。这将通过对一组经历过两次或两次以上肝脏活检的不同表型的非酒精性脂肪肝受试者在基线肝活检时提取的血浆进行脂质组学分析来实现。目标3将定义与治疗诱导的NASH改善相关的循环脂信号。这将利用在NASH CRN登记参加临床试验的受试者的方案驱动的活检过程中获得的独特样本集。这些研究将进一步创新，将由Liid_Maps开发的最先进的分析平台应用于NASH的诊断开发。初步数据支持拟议研究和目标的可行性。这些研究将满足诊断准确性评估(QUADAS)的所有质量指标，并将通过开发一个允许对NASH进行护理点评估的诊断平台，对该领域产生强大的积极影响。这将增加获得护理的机会，并最终改善人民的健康，从而与国家卫生研究院的使命保持一致。

 DESCRIPTION (provided by applicant): Nonalcoholic steatohepatitis (NASH) is an aggressive form of nonalcoholic fatty liver disease (NAFLD) that affects 3-4% of the adult population and progresses to cirrhosis in 15-20% of affected subjects. There is currently no approved therapy for NASH and the only accurate method to diagnose this condition is a liver biopsy which is invasive, painful and occasionally associated with mortality. The lack of a "point-of-care" diagnostic tool to diagnose NASH, to assess disease progression versus regression and response to various therapeutics is considered by many to be the most important barrier towards large scale identification of affected individuals and for drug-development against NASH. This proposal represents a multi-PI effort to develop a lipidomics-based biomarker panel to fill these gaps in knowledge. Dr. Sanyal (PI) from the NIDDK NASH Clinical Research Network (CRN) will lead this effort and Dr. Dennis (Co-PI) who previously led the NIGMS LIPID_MAPS consortium will lead the lipid analysis. The NASH CRN data coordinating center (DCC) will continue to serve as the DCC for this proposal. The studies will draw from the NASH CRN biorepository which contains plasma drawn at the time of a liver biopsy from over 2000 highly phenotyped subjects with NAFLD. Three specific aims will test the hypothesis that changes in lipid metabolism in NAFLD allow identification of a circulating lipid signature diagnostic of NASH, disease progression and response to specific therapies. Aim 1 will define and validate a circulating lipid profile diagnostic of underlying NASH and its severity. A model building cohort and two validation cohorts will be studied. The model building cohort will include subjects with and without NAFLD. The validation cohort will include: (1) a group of subjects with varying phenotypes of NAFLD and age, gender, race and weight-matched controls without NAFLD, and (2) a prospective group of subjects in a "real-world" setting who are going to receive a clinically-indicated liver biopsy for suspected NASH. Aim 2 will define changes in circulating lipids diagnostic of disease progression in NASH. This will be accomplished by performing lipidomic analyses on plasma drawn at the time of baseline liver biopsies in a cohort of subjects with varying phenotypes of NAFLD who have undergone two or more liver biopsies. Aim 3 will define the circulating lipid signature associated with treatment-induced improvement of NASH. This will utilize unique sample-sets obtained during protocol-driven biopsies from subjects enrolled in clinical trials by the NASH CRN. The studies will further innovate by applying the state-of-the-art analytic platforms developed by LIPID_MAPS for diagnostics development for NASH. Preliminary data support the feasibility of the proposed studies and aims. These studies will meet all of the quality metrics for accuracy assessment of diagnostics (QUADAS) and will have a strong positive impact on the field by allowing development of a diagnostic platform that will permit point of care evaluation of NASH. This will enhance access to care and eventually improve the health of the people thereby aligning with the mission of the NIH.