Role of CD4 T cells in the pathogenesis of non-alcoholic steatohepatitis

项目摘要/摘要 非酒精性脂肪性肝炎(NASH)相关的肝硬变可能是肝脏的主要适应症 到2020年在美国进行移植。尽管发病率不断上升，但机制尚不清楚 NASH发病机制的研究阻碍了我们制定有效的诊断和治疗策略的能力。 有大量的科学证据表明，饮食诱导的肠道生物失调， NASH发生中肠上皮屏障功能障碍和CD4T细胞诱导的肝脏炎症。我的 初步数据显示饮食诱导的肝脏和肝脏促炎CD4T细胞增加的作用 NASH小鼠模型的肠黏膜炎症。这些新奇的数据与出版的 文献为进一步研究CD4T细胞介导的 NASH患者的肝脏炎症和肠上皮屏障破坏。在目标1中，我将确定肠子是如何 微生物区系促进CD4T细胞介导的肠上皮屏障破坏。在《目标2》中，我将调查 饮食诱导的CD4T细胞活化和转运到肠粘膜的机制及其作用 发挥调节肠道上皮屏障完整性的作用。在目标3中，我将重点介绍CD4T细胞的机制- NASH发展过程中介导的肝脏炎症。鉴于CD4T细胞在免疫调节中的重要作用 NASH患者的肝脏和肠道免疫、肠道生物失调与NASH的相关性及其治疗潜力 针对肠道微生物区系和免疫细胞，这一建议代表了NASH的一个新视角，即 具有很强的创新性和临床相关性。 K01奖将让我与世界领先的肝病和免疫学专家一起工作，因为我 追求成为一名独立的生物医学研究者的目标。非同寻常的导师关系 这将提高我作为调查人员的技能，并回答重要的问题 与肝脏的代谢性疾病有关。此外，这一奖项将极大地促进我的肝脏训练 在弗兰克·阿纳尼亚博士的指导下，疾病。作为一名内科科学家，他做出了重大贡献 在代谢性肝病领域的贡献，Anania博士和他的实验室提供了理想的环境 学习纳什。我的导师委员会包括世界著名的T细胞免疫学家拉菲·艾哈迈德博士，他将 为我提供重要的科学建议和获取尖端免疫学工具的关键途径 全面研究T细胞在NASH中的作用的技术。阿拉什博士也是我委员会的成员 Grakoui博士说，他是研究肝脏T细胞及其在慢性病毒感染中的作用的领先专家。此外， 埃默里大学医学院优越的教育环境将通过以下方式加强我的培训 提供机构计划、设施和协作机会。K01奖将提供 在我职业生涯的这个关键阶段，给予了我重要的支持，使我能够做出实质性的学习承诺 免疫调节在肝脏代谢性疾病中的作用

PROJECT SUMMARY/ABSTRACT Non-alcoholic steatohepatitis (NASH)-related cirrhosis is likely to be the leading indication for liver transplantation in the United States by 2020. Despite the growing incidence, a lack of clarity in the mechanisms of NASH pathogenesis has hindered our ability to develop effective diagnostic and therapeutic strategies. There is substantial scientific evidence suggesting a strong relationship between diet-induced gut dysbiosis, intestinal epithelial barrier dysfunction and CD4 T cell-induced hepatic inflammation in NASH development. My preliminary data reveal a role for diet-induced increases in pro-inflammatory CD4 T cells in hepatic and intestinal mucosal inflammation in a mouse model of NASH. These novel data along with the published literature provide a strong premise to further investigate the mechanistic link between CD4 T cell-mediated hepatic inflammation and intestinal epithelial barrier disruption in NASH. In Aim 1, I will determine how the gut microbiota facilitate CD4 T cell-mediated intestinal epithelial barrier disruption. In Aim 2, I will investigate mechanisms of diet-induced CD4 T cell activation and trafficking to the gut mucosa, and the role CD4 T cells play in regulating intestinal epithelial barrier integrity. In Aim 3, I will focus on the mechanisms of CD4 T cell- mediated hepatic inflammation in NASH development. Given the importance of CD4 T cells in the regulation of hepatic and intestinal immunity in NASH, the relevance of gut dysbiosis to NASH, and the therapeutic potential of targeting gut microbiota and immune cells, this proposal represents a new perspective in NASH that is highly innovative and clinically relevant. A K01 award will allow me to work alongside the world's leading experts in liver disease and immunology as I pursue my goal to become an independent biomedical investigator. The extraordinary mentorship relationships that will develop will improve my skills as an investigator as well as answer significant important questions related to metabolic diseases of the liver. Further, this award will immeasurably advance my training in liver disease under the guidance of Dr. Frank Anania. As a physician-scientist who has made significant contributions in the field of metabolic liver disease, Dr. Anania and his lab provide an ideal environment to study NASH. My mentorship committee includes world-renowned T cell immunologist, Dr. Rafi Ahmed, who will provide me with important scientific counsel and critical access to cutting-edge immunological tools and techniques to comprehensively investigate the role of T cells in NASH. Also on my committee is Dr. Arash Grakoui, the nation's leading expert on hepatic T cells and their role in chronic viral infection. Moreover, the exceptional educational environment at Emory University School of Medicine will augment my training by providing institutional programs, facilities, and opportunities for collaboration. A K01 award will provide significant support at this pivotal stage of my career, allowing me to make a substantial commitment to study the role of immune regulation in metabolic diseases of the liver.