Biological Determinants of Steatohepatitis after Adolescent Bariatric Surgery

极度肥胖的青少年有明显更高的肝脂肪变性（脂肪肝）患病率， 非酒精性脂肪性肝炎（NASH），一种慢性和潜在进行性肝病， 发病率和死亡率增加。减肥手术对极度肥胖青少年的影响 NASH的结局尚不清楚，肥胖治疗诱导的体重减轻后结局的生物学预测因子 手术尚未定义。本提案将通过以下方式解决这些知识差距：1）确定 极端肥胖患者通过减肥手术诱导体重减轻后肝脂肪变性和NASH的结局 青少年和2）定义脂肪变性，炎症和 纤维化这些目标将通过在一个队列中进行纵向观察性研究来实现， 接受减肥手术的患有NASH的极度肥胖青少年。人体测量，特异性血清 将在手术前和手术后的体重减轻前调查实验室参数和肝组织学。生物 肝脏对体重减轻的组织学反应的预测因子将通过测量 肝脂肪变性和NASH的假设风险因素，包括中心性肥胖，胰岛素抵抗， 循环游离脂肪酸和选定的脂肪细胞因子。研究肝细胞癌的分子决定因素， 反应，肝组织表达的基因调节脂肪生成，炎症，凋亡和纤维化将 被衡量。一个为期五年的指导计划提出，将结合教学和研究 培训，并将由儿科肝病和遗传学领域的知名研究者指导。 肥胖候选人的总体职业目标是成为一个独立和创新的临床 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。到 为了实现这一目标，她将在1）人类基因组研究的原则，2） 肥胖症病理生理学的分子方面和3）进行临床试验，以便能够翻译 把新的研究成果带回到床边人类研究道德行为的培训将 包括.拟议的研究将产生重要的洞察生物决定因素的反应， 肝脏脂肪变性和NASH，同时提供候选药物 作为一名临床研究科学家，需要接受必要的培训，以建立独立性。研究提出 因为它将确定潜在的治疗靶点， 脂肪变性和炎症，并阻断进展为晚期纤维化。此外，持久性的风险因素 将确定减肥手术后的肝脏疾病。这项研究的长期影响将使 制定更加个性化和预测性的诊断和治疗战略， NASH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.