The effects of bile acid receptor activation on non-alcoholic fatty liver disease

胆汁酸受体激活对非酒精性脂肪肝的影响

• 批准号: 8581540
• 负责人: RACHEL MCMAHAN
• 金额: $ 9.93万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8581540
• 关键词: Advisory Committees; Affect; Agonist; American; Anti-Inflammatory Agents; Anti-inflammatory; Area; Award; Benign; Bile Acids; Biology; Bone Marrow; Cells; Cicatrix; Cirrhosis; Colorado; Cytoplasm; Data; Development; Development Plans; Diet; Disease; Disease model; Fatty acid glycerol esters; Funding; Gastroenterology; Genetic; Goals; Health; Hepatic; Hepatocyte; Histologic; ITGAM gene; Immune; Immune response; Immunology; Individual; Inflammation; Inflammatory; Inflammatory Response; Interdisciplinary Study; Interleukin-10; Kupffer Cells; Lead; Link; Liver; Liver Failure; Liver diseases; Mediator of activation protein; Medical; Mentored Research Scientist Development Award; Mentors; Metabolism; Modeling; Mus; Myeloid Cells; Nuclear Hormone Receptors; Nuclear Receptors; Obesity; Obesity associated disease; Pathogenesis; Pathway interactions; Phenotype; Play; Population; Production; Publications; Receptor Activation; Recording of previous events; Relative (related person); Research; Research Personnel; Role; Scientist; Signal Transduction; Steatohepatitis; System; Tissues; Training; Triglycerides; Universities; career; career development; cell type; clinically relevant; cytokine; db/db mouse; design; disease phenotype; experience; glucose metabolism; human GPR4 protein; improved; insight; instructor; intrahepatic; lipid metabolism; liver function; liver inflammation; liver injury; macrophage; member; migration; monocyte; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; public health relevance; receptor; research study; treatment response; treatment strategy

DESCRIPTION (provided by applicant): This is an application by Dr. Rachel McMahan for the Mentored Research Scientist Development Award (K01). Dr. McMahan is an Instructor in the Department of Gastroenterology at the University of Colorado Anschutz Medical Campus. The candidate's career goal is to become an established independent investigator with a research team dedicated to understanding the role of the immune response in non-alcoholic fatty liver disease (NAFLD) and other obesity-related diseases. NAFLD affects a large proportion of the American population and can lead to steatohepatitis, cirrhosis and eventual liver failure. In preliminary studies it was determined that administration of a bile acid (BA) receptor agonist to obese db/db mice significantly improved the histologic features of NAFLD and decreased liver inflammation. Interestingly, the treatment led to considerable increases in the Ly6Clow monocyte population within the liver and an increase in IL-10 production by monocytes. While, Ly6Chigh monocytes have recently been implicated as important mediators for obesity-associated liver inflammation, it has been suggested that Ly6Clow monocytes may inhibit the inflammatory response and differentiate into alternatively activated macrophages (AAM). The studies proposed here will further evaluate the effects of BA activation on monocytes and establish the role of these cells in NAFLD. Aim 1 will determine if BA receptor activation alters monocyte differentiation, survival and/or migration to the liver. Aim 2 will evaluate if monocytes can in turn protect against NAFLD and Aim 3 will investigate if IL-10 plays a role in disease improvement. These studies will provide novel insight in to how BA receptor activation coordinates the immune phenotype of monocytes and macrophages and will help in identifying potential targeting strategies for treatment of NAFLD. The candidate will utilize the results from these studies to develop new hypotheses and apply for R01 support. Dr. McMahan has extensive training in immunology and this award will provide her with the opportunity to expand her scientific expertise into the areas of metabolism and obesity. She will be mentored by Dr. Hugo Rosen, an expert in the field of liver immunology with an excellent funding history and publication record. In addition, she will be co-mentored by Dr. Moshe Levi who has extensive experience in obesity, metabolism and nuclear receptor biology. She has assembled a strong interdisciplinary advisory committee that includes experts in the areas of murine macrophage biology (Dr. Cynthia Ju) and nuclear receptors (Dr. Suchy). This committee has helped Dr. McMahan develop a strong career development plan and their expertise will allow for her to successfully transition into a career as independent scientist in this exciting area of interdisciplinary research.

描述(申请人提供)：这是雷切尔·麦克马汉博士申请的导师研究科学家发展奖(K01)。麦克马汉博士是科罗拉多大学安舒茨医学院胃肠病系的讲师。候选人的职业目标是成为一名成熟的独立研究员，拥有一个致力于了解免疫反应在非酒精性脂肪性肝病(NAFLD)和其他肥胖相关疾病中的作用的研究团队。非酒精性脂肪肝影响了很大一部分美国人，并可能导致脂肪性肝炎、肝硬变和最终的肝功能衰竭。在初步研究中，已经确定给肥胖的db/db小鼠注射胆汁酸(BA)受体激动剂显着改善了NAFLD的组织学特征，并减少了肝脏炎症。有趣的是，治疗导致肝脏内Ly6Clow单核细胞数量显著增加，单核细胞产生IL-10增加。虽然Ly6Chigh单核细胞最近被认为是肥胖相关肝脏炎症的重要介质，但有研究表明Ly6Clow单核细胞可能抑制炎症反应，并分化为交替激活的巨噬细胞(AAM)。本文提出的研究将进一步评估BA激活对单核细胞的影响，并确定这些细胞在NAFLD中的作用。目的1确定BA受体激活是否改变单核细胞的分化、存活和/或向肝脏的迁移。Aim 2将评估单核细胞是否能反过来预防NAFLD，Aim 3将研究IL-10是否在疾病改善中发挥作用。这些研究将为BA受体激活如何协调单核细胞和巨噬细胞的免疫表型提供新的见解，并将有助于确定治疗NAFLD的潜在靶向策略。候选人将利用这些研究的结果来开发新的假设并申请R01支持。McMahan博士在免疫学方面接受了广泛的培训，这一奖项将为她提供机会，将她的科学专长扩展到新陈代谢和肥胖领域。她将得到雨果·罗森博士的指导，他是肝脏免疫学领域的专家，拥有出色的资助历史和出版记录。此外，她还将得到摩西·利维博士的共同指导，后者在肥胖、新陈代谢和核受体生物学方面拥有丰富的经验。她组建了一个强大的跨学科咨询委员会，成员包括小鼠巨噬细胞生物学(Cynthia Ju博士)和核受体(Suchy博士)领域的专家。该委员会帮助McMahan博士制定了强有力的职业发展计划，他们的专业知识将使她能够在这一令人兴奋的跨学科研究领域成功过渡到独立科学家的职业生涯。