Biological Determinants of Steatohepatitis after Adolescent Bariatric Surgery

极度肥胖的青少年肝脏脂肪变性(脂肪肝)的患病率明显更高， 非酒精性脂肪性肝炎(NASH)，一种慢性和潜在的进行性肝病，与 发病率和死亡率增加。减肥手术对重度肥胖青少年的影响 NASH的结局尚不清楚，减肥后预后的生物学预测因子 外科手术还没有被定义。该提案将通过以下方式解决这些知识差距：1)确定 超重肥胖者减肥后肝脏脂肪变性和非酒精性脂肪肝的转归 和2)确定脂肪变性、炎症和脂肪变性改变的关键生物学决定因素 纤维化症。这些目标将通过在一群人中进行纵向观察研究来实现 患有NASH的极度肥胖的青少年正在接受减肥手术。人体测量学，特定血清 实验室参数和肝脏组织学检查将在手术前后进行。生物学 肝脏对体重减轻的组织学反应的预测因子将通过测量 假设的肝脏脂肪变性和NASH的危险因素，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。研究肝脏的分子决定因素 肝组织表达调控脂肪生成、炎症、细胞凋亡和纤维化的基因将 被测量。一个五年的指导计划被提出，它将包括教学和研究。 培训，并将由在儿科肝病和遗传学方面的知名研究人员指导 肥胖。候选人的首要职业目标是成为一名独立和创新的临床医生 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。至 为了实现这一目标，她将在1)人类基因组研究原理方面进行高级培训，2) 肥胖症病理生理学的分子方面以及3)进行临床试验，以便能够翻译 新奇的研究成果回到床边。人类研究的道德行为方面的培训将是 包括在内。这项拟议中的研究将对生物决定因素的反应产生重要的洞察力 手术后体重减轻后肝脏脂肪变性和NASH，同时提供候选 受过必要的培训，以确立作为临床研究科学家的独立性。这项研究建议 具有额外的重要意义，因为它将识别潜在的治疗靶点， 脂肪变性和炎症，并阻止进展为晚期纤维化。此外，影响持久性的风险因素 减肥手术后肝脏疾病的风险将被确定。这项研究的长期影响将是 制定更个性化和更具预测性的诊断和治疗策略，以预防和 纳什的治疗。

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.