Biological Determinants of Steatohepatitis after Adolescent Bariatric Surgery

描述(由申请人提供)： 极度肥胖的青少年肝脏脂肪变性(脂肪肝)和非酒精性脂肪性肝炎(NASH)的患病率明显更高，这是一种与发病率和死亡率增加相关的慢性和潜在进行性肝病。在极度肥胖的青少年中，减肥手术对NASH结果的影响尚不清楚，也没有确定减肥手术后体重减轻后的生物学预测因素。这项建议将通过1)确定极端肥胖青少年减肥手术后肝脏脂肪变性和NASH的结果，以及2)确定脂肪变性、炎症和纤维化变化的关键生物学决定因素，来解决这些知识差距。这些目标将通过在一组接受减肥手术的极度肥胖的NASH青少年队列中进行纵向观察研究来实现。对手术前后的体重减轻情况进行人体测量、特定的血清实验室参数和肝组织学检查。通过测量肝脏脂肪变性和NASH的假设风险因素的变化，将确定肝脏对体重减轻的组织学反应的生物学预测因素，包括中心性肥胖、胰岛素抵抗、循环中的游离脂肪酸和选定的脂肪细胞因子。为了研究肝脏反应的分子决定因素，将测量调控脂肪生成、炎症、细胞凋亡和纤维化的基因在肝脏组织中的表达。一项为期五年的指导计划被提出，该计划将包括教学和研究培训，并将由儿科肝病和肥胖遗传学方面的知名研究人员指导。候选人的首要职业目标是成为一名独立和创新的临床研究科学家，专注于减少与儿童和青少年肥胖相关的疾病负担。为了实现这一目标，她将在1)人类基因组研究原理，2)肥胖症病理生理学的分子方面，以及3)临床试验方面进行高级培训，以便能够将新的研究成果转化回床边。人类研究的道德行为方面的培训将包括在内。这项拟议的研究将对手术减肥后肝脏脂肪变性和NASH反应的生物学决定因素产生重要的见解，同时为候选人提供必要的培训，以建立作为临床研究科学家的独立性。提出的这项研究还具有重要意义，因为它将确定潜在的治疗靶点，可能减少肝脏脂肪变性和炎症，并阻止进展为晚期纤维化。此外，将确定减肥手术后肝脏疾病持续存在的危险因素。这项研究的长期影响将是为NASH的预防和治疗开发更个性化和预测性的诊断和治疗策略。

DESCRIPTION (provided by applicant): Extremely obese adolescents have a markedly higher prevalence of hepatic steatosis (fatty liver) and nonalcoholic steatohepatitis (NASH), a chronic and potentially progressive liver disease associated with increased morbidity and mortality. The effect of bariatric surgery in extremely obese adolescents on outcome of NASH is unknown, and biological predictors of outcome after weight loss induced by bariatric surgery have not been defined. This proposal will address these gaps in knowledge by 1) determining the outcome of hepatic steatosis and NASH after weight loss induced by bariatric surgery in extremely obese adolescents and 2) defining the critical biological determinants of changes in steatosis, inflammation and fibrosis. These goals will be accomplished by conducting a longitudinal observational study in a cohort of extremely obese adolescents with NASH undergoing bariatric surgery. Anthropometries, specific serum laboratory parameters and hepatic histology will be surveyed pre and post-surgical weight loss. Biological predictors of the histologic response of the liver to weight loss will be determined by measuring changes in hypothesized risk factors for hepatic steatosis and NASH, including central adiposity, insulin resistance, circulating free fatty acids and selected adipocytokines. To investigate molecular determinants of hepatic response, hepatic tissue expression of genes regulating lipogenesis, inflammation, apoptosis and fibrosis will be measured. A five year mentored program is proposed that will incorporate both didactic and research training and will be guided by well-established investigators in pediatric liver disease and in the genetics of obesity. The candidate's overarching career goal is to become an independent and innovative clinical research scientist focused on reducing the disease burden related to pediatric and adolescent obesity. To achieve this goal, she will pursue advanced training in 1) principles of human genomic research, 2) molecular aspects of obesity pathophysiology and 3) conduct of clinical trials in order to enable translation of novel research findings back to the bedside. Training in the ethical conduct of human research will be included. The proposed research will yield important insight into biological determinants of the response of hepatic steatosis and NASH after surgically-induced weight loss, while concurrently providing the candidate with the needed training to establish independence as a clinical research scientist. The research proposed is additionally significant because it will identify potential therapeutic targets that may reduce hepatic steatosis and inflammation, and block progression to advanced fibrosis. Further, risk factors for persistence of liver disease after bariatric surgery will be identified. The long-term impact of this study will be to enable development of more personalized and predictive diagnostic and therapeutic strategies for prevention and treatment of NASH.