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

项目总结/摘要 该提案的主要目标是将首席研究员迈克尔·汤普森博士培养成为一名 肝病学研究领域的独立医师科学家。Michael曾获得PhD 细胞和分子病理学培训，重点是肝病。目前，他已经完成了 在儿科内分泌临床培训，并设计了一个5年的职业发展计划，以提供 胆汁酸代谢和微生物组研究的额外培训。在这个职业发展的最后 获奖后，他将成为一名独立的调查员，拥有自己的实验室项目， 肝病的起源华盛顿大学胃肠病学主任尼古拉斯·戴维森博士将指导 PI。Davidson博士是肠道和肝脏胆汁酸代谢研究的著名领导者， 经验丰富的导师。华盛顿大学儿科胃肠病学主任菲尔·塔尔博士将担任 私家侦探的共同导师Tarr博士是微生物组研究的公认领导者，这是本研究的主要重点。 提议PI将利用丰富的基础科学和临床资源， 华盛顿大学发展他自己的临床相关的基础研究计划。 肥胖症及其并发症影响着7800万成年人和1300万儿童， 每年影响2.0万亿美元。越来越多的证据支持，子宫内和围产期事件驱动的风险， 胰岛素抵抗和肥胖相关的并发症，如非酒精性脂肪肝（NAFLD）， 后代我们的初步研究结果表明，胆汁酸稳态的改变与此相关， 增加风险。该提案将重点关注定义胆汁中观察到的变化背后的机制， 酸性体内平衡我将利用一个已建立的母体高脂肪/高糖饮食暴露模型来测试这一点 假说.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/运输，以确定哪些因素导致胆汁酸池大小和组成增加。在 第二个目标，我将确定微生物组的垂直传播是否发生在代际之间， 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 第三个目标，我将评估靶向胆汁酸池大小或池组成作为 肥胖母鼠后代代谢性肝病的预防方法。具体来说，我会把后代 与胆汁酸螯合剂（考来烯胺）或亲水性胆汁酸（UDCA）接触， 之后我会评估胰岛素抵抗和脂肪变性确定潜在致病性改变， 胆汁酸池组成、代谢和/或转运将支持进一步的假设驱动研究设计 以确定疾病进展风险增加的机制。一旦一种机械联系被证实 后代胆汁酸代谢改变与NAFLD进展风险之间的关系， 设计基于胆汁酸的预防性治疗，以预防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.