Impact of Maternal Obesity on Offspring Non-alcoholic Fatty Liver Disease: Role of Bile Acid Homeostasis and Microbiome

项目摘要/摘要 这项提案的主要目标是将首席研究员迈克尔·汤普森博士发展成为一名 肝病研究领域的独立内科科学家。迈克尔之前获得了博士学位 细胞和分子病理学方面的培训，重点是肝脏疾病。目前，他已经完成了 接受儿科内分泌学临床培训，并设计了5年职业发展计划，以提供 胆汁酸代谢和微生物组研究方面的额外培训。在这个职业发展的末尾 获奖后，他将成为一名独立的调查员，拥有自己的实验室计划，评估发展 肝病的起源。华盛顿大学消化科主任尼古拉斯·戴维森博士将指导 圆周率。戴维森博士是肠道和肝脏胆汁酸代谢研究的知名领导者， 经验丰富的导师。华盛顿大学儿科消化科主任菲尔·塔尔博士将担任 私募基金的联合导师。塔尔博士是微生物组研究领域公认的领导者，这是这项研究的主要关注点。 求婚。该研究所将利用丰富的基础科学和临床资源，网址为 华盛顿大学开发自己的临床相关基础研究计划。 肥胖及其并发症影响着7800万成年人和1300万儿童，据估计， 每年2.0万亿美元的影响。越来越多的证据支持，宫内和围产期事件会导致 胰岛素抵抗和肥胖相关并发症，如非酒精性脂肪肝(NAFLD) 后代。我们的初步发现表明胆汁酸平衡的改变与此有关。 风险增加。这项提案将侧重于确定观察到的胆汁变化背后的机制。 酸性动态平衡。我将利用已建立的母亲高脂肪/高糖饮食暴露的模型来测试这一点 假设。在第一个目标中，我将评估胆固醇吸收、胆汁酸排泄和胆汁酸 代谢/转运，以确定哪些因素导致胆酸池的大小和组成增加。在……里面 第二个目标，我将定义微生物组的垂直传播是否发生在世代之间，以及 微生物组的变化是否会影响后代的胆汁酸代谢和代谢性肝病。在……里面 第三个目标，我将评估以胆酸池大小或池组成为目标的有效性 肥胖母鸡代谢性肝病后代的预防方法。具体地说，我会治疗后代 在喂食西方饮食之前使用胆汁酸隔离剂(胆碱胺)或亲水性胆汁酸(UDCA)， 之后我会评估胰岛素抵抗和脂肪变性。发现潜在的致病基因改变 胆酸池的组成、代谢和/或转运将支持进一步的假设驱动的研究设计 以确定疾病进展风险增加的机制。一旦机械连接被证明 在后代胆汁酸代谢改变和NAFLD进展风险之间，这一信息将被用于 设计以胆汁酸为基础的预防性治疗，以防止高危患者的疾病进展。

PROJECT SUMMARY/ABSTRACT The primary goal of this proposal is to develop the principal investigator, Dr. Michael Thompson, into an independent physician scientist in the field of hepatology research. Michael has previously received PhD training in cellular and molecular pathology with a focus on liver disease. At the current time, he has completed clinical training in Pediatric Endocrinology and has designed a 5 year career development plan to provide additional training in bile acid metabolism and microbiome research. At the end of this career development award, he will become an independent investigator with his own lab program evaluating the developmental origins of liver disease. Dr. Nicholas Davidson, Chief of Gastroenterology at Washington University, will mentor the PI. Dr. Davidson is a well-known leader in intestinal and hepatic bile acid metabolism research and an experienced mentor. Dr. Phil Tarr, Chief of Pediatric Gastroenterology at Washington University, will serve as co-mentor for the PI. Dr. Tarr is a recognized leader in microbiome research which is a primary focus of this proposal. The PI will take advantage of the abundant basic science and clinical resources available at Washington University to develop his own clinically relevant basic research program. Obesity and its complications affect 78 million adults and 13 million children with an estimated economic impact of $2.0 trillion per year. Growing evidence supports that in utero and perinatal events drive risk for insulin resistance and obesity associated complications such as nonalcoholic fatty liver disease (NAFLD) in the offspring. Our preliminary findings indicate that alterations in bile acid homeostasis are associated with this increased risk. This proposal will focus on defining the mechanisms behind the observed alterations in bile acid homeostasis. I will utilize an established model of maternal high fat/high sugar diet exposure to test this hypothesis. In the first aim, I will evaluate cholesterol absorption, bile acid excretion, and bile acid metabolism/transport to define which are contributing to the increased bile acid pool size and composition. In the second aim, I will define whether vertical transmission of the microbiome occurs across generations and whether changes in the microbiome impact bile acid metabolism and metabolic liver disease in the offspring. In the third aim, I will evaluate the efficacy of targeting the bile acid pool size or pool composition as a preventative approach for metabolic liver disease offspring of obese dams. Specifically, I will treat offspring with a bile acid sequestrant (cholestyramine) or a hydrophilic bile acid (UDCA) prior to feeding a western diet, after which I will evaluate insulin resistance and steatosis. Identification of potentially pathogenic alterations in bile acid pool composition, metabolism, and/or transport will support further hypothesis driven research design to identify the mechanism of increased risk for disease progression. Once a mechanistic link is proven between altered bile acid metabolism in offspring and risk for NAFLD progression, this information will be used to design bile acid based preventative therapies to prevent disease progression in at risk patients.