Biological Determinants of Steatohepatitis after Adolescent Bariatric Surgery

描述（由申请人提供）： 极度肥胖的青少年有明显更高的肝脂肪变性（脂肪肝）和非酒精性脂肪性肝炎（NASH）的患病率，NASH是一种慢性和潜在的进行性肝病，与发病率和死亡率增加相关。在极度肥胖的青少年中，减肥手术对NASH结局的影响尚不清楚，减肥手术诱导的体重减轻后结局的生物学预测因子尚未确定。该提案将通过以下方式解决这些知识空白：1）确定极度肥胖青少年通过减肥手术诱导的体重减轻后肝脂肪变性和NASH的结局; 2）定义脂肪变性、炎症和纤维化变化的关键生物学决定因素。这些目标将通过在接受减肥手术的极度肥胖NASH青少年队列中进行纵向观察性研究来实现。将在手术前和手术后的体重减轻中调查人体测量、特定血清实验室参数和肝脏组织学。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）的变化来确定肝脏对体重减轻的组织学反应的生物学预测因子。为了研究肝脏反应的分子决定因素，将测量调节脂肪生成、炎症、凋亡和纤维化的基因的肝组织表达。一个为期五年的指导计划，将包括教学和研究培训，并将由在儿科肝病和肥胖遗传学方面的成熟研究人员指导。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）人类基因组研究的原则，2）肥胖病理生理学的分子方面和3）临床试验的进行，以使新的研究结果的翻译回到床边进行高级培训。将包括人类研究道德行为方面的培训。拟议的研究将对肝脏脂肪变性和NASH在药物诱导的体重减轻后的反应的生物学决定因素产生重要的见解，同时为候选人提供所需的培训，以建立作为临床研究科学家的独立性。这项研究还具有重要意义，因为它将确定可能减少肝脏脂肪变性和炎症的潜在治疗靶点，并阻止进展为晚期纤维化。此外，将确定减肥手术后肝病持续存在的风险因素。这项研究的长期影响将是能够开发更个性化和预测性的诊断和治疗策略，以预防和治疗NASH。

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.