The role of CD8+ T cells in the development of Nonalcoholic Fatty Liver Disease

CD8 T 细胞在非酒精性脂肪肝发展中的作用

• 批准号: 8616468
• 负责人: Arion Kennedy
• 金额: $ 11.3万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-15 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8616468
• 关键词: Academia; Academic Medical Centers; Address; Adipose tissue; Adoptive Cell Transfers; Animal Model; Animals; Antibodies; Attention; Award; Benign; CD8B1 gene; Carcinoma; Cardiovascular Diseases; Cell physiology; Cells; Characteristics; Chronic; Cirrhosis; Clinical Research; Communication; Core Facility; Coronary; Country; Cytoplasm; Data; Deposition; Development; Diabetes Mellitus; Disease; Environment; Fatty Liver; Fibrosis; Flow Cytometry; Future; Gene Expression; Goals; Grant; Health Care Costs; Hepatic; Hepatocyte; Histopathology; Hyperlipidemia; Immune; Immune system; Incidence; Infiltration; Inflammation; Inflammatory; Insulin Resistance; Interleukin-10; K-Series Research Career Programs; Knowledge; Kupffer Cells; Laboratories; Lead; Liver; Liver Fibrosis; Liver diseases; Lymphocyte; Lymphocyte Subset; Mentors; Mentorship; Metabolic Diseases; Modeling; Molecular; Mus; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Phenotype; Population; Postdoctoral Fellow; Prevalence; Prevention; RNA Sequences; Research; Research Personnel; Research Project Grants; Resource Sharing; Risk Factors; Role; Scientist; Societies; Solid; T-Lymphocyte; Techniques; Testing; Tissue Inhibitor of Metalloproteinase-1; Training; Triglycerides; Work; Wound Healing; abstracting; base; career; cytotoxic; disorder prevention; effective therapy; experience; in vivo; insight; liver inflammation; liver injury; macrophage; monocyte; mouse model; non-alcoholic fatty liver; nonalcoholic steatohepatitis; prevent; response; skills; therapeutic target

PROJECT SUMMARY/ABSTRACT Candidate My career goal is to direct a successful laboratory in academia, incorporating cellular, animal, and clinical research to address the impact of the innate immune system on obesity and associated metabolic disorders and the impact of nutrients have on immune cell function. I am applying for the Mentored Career Development Award because it offers an excellent opportunity to transition into an independent investigator. Currently I am a post-doctoral trainee in Dr. Alyssa Hasty's laboratory where I have been able to enhance my molecular techniques and gain experience working with immune cells and animal models of obesity and hyperlipidemia. I have been able to establish my own independent research project aimed at the role of hepatic CD8+ T cells in the development of non-alcoholic fatty liver disease. A number of research skills will be obtained under the present proposal, including RNA sequencing, antibody depletion, adoptive cell transfer studies, and flow cytometry. Also under the mentorship of Dr. Hasty, I will continue to obtain training in scientific communication and professional skills, necessary to become an independent investigator. The scientific environment of Vanderbilt University Medical Center is ideally suited to help me achieve my long career goal to study the immune system and metabolic disease. There are numerous shared resources and core facilities (VANTAGE core, Flow cytometry core) and a vast number of collaborative opportunities available. My previous training opportunities and scientific skills have provided me with a solid background in obesity, diabetes, cardiovascular disease, and nonalcoholic fatty liver disease, necessary to execute my proposed studies. Thus, the knowledge and scientific skills obtained during this training award will help prepare me for my future goal of becoming an independent research scientist in academia. Abstract With the vast increase of metabolic disease, nonalcoholic fatty liver disease (NAFLD) is progressively more common in today's society. NAFLD ranges from hepatic steatosis to cirrhosis. Nonalcoholic steatohepatitis (NASH) is characterized by hepatic steatosis and mixed inflammatory cell infiltration and is a major predictor of fibrotic progression. Recently, NASH has been identified as a risk factor for cardiovascular disease. It is well known that immune cells are key contributors to inflammation and fibrosis. While much attention has been placed on the role of kupffer cells in NAFLD, limited attention has been placed on the subpopulations of lymphocytes and their contribution to NAFLD. Under obese conditions, CD8+ T cells have been found to regulate macrophage infiltration in adipose tissue. Our preliminary data are the first to demonstrate that hyperlipidemia induces an early infiltration of hepatic CD8+ T cells that express a unique Th2 and cytotoxic phenotype. This hepatic lymphocyte infiltration correlates with an increase in hepatic inflammatory monocytes and fibrogenic markers. However, the distinct role of these immune cells in NASH is unclear. Thus, the Specific Aims of this project are: 1) To identify the phenotype of hepatic CD8+ T-cell populations during the transition from steatosis to NASH; 2) To determine in vivo the extent to which CD8+ T-cells impact the development of NASH; 3)To determine in vivo the extent to which IL-10 impacts the transition from hepatic steatosis to NASH. Our hypotheses are 1) early infiltrating CD8+ T-cells express a cytotoxic and Th2 phenotype which drives the recruitment and the profibrogenic phenotype in macrophages; 2) depletion of CD8+ T cells will reduce the recruitment and profibrogenic phenotype of macrophages; while addition of CD8+ T cells will increase the profibrogenic phenotype of macrophages under conditions of hepatic steatosis; 3) depletion of IL-10 will decrease the profibrogenic phenotype in hepatic macrophages under NAFLD conditions. Data obtained from this proposal are expected to provide critical insight for the potential development of therapeutic targets for the prevention and treatment of NASH, and reduce health care costs related to these disorders.

项目摘要/摘要 候选人 我的职业目标是指导一个在学术界成功的实验室，并结合了蜂窝， 动物和临床研究，以解决先天免疫系统对肥胖和 相关的代谢性疾病和养分的影响对免疫细胞功能。我是 申请指导职业发展奖，因为它提供了绝佳的机会 过渡到独立研究者。目前，我是博士博士的博士后学员。 Alyssa Hasty的实验室，我能够增强我的分子技术和 获得与肥胖和高脂血症的免疫细胞和动物模型一起工作的经验。我 已经能够建立我自己的独立研究项目，旨在发挥肝作用 CD8+ T细胞在非酒精性脂肪肝病的发展中。许多研究技能 将根据本提案获得，包括RNA测序，抗体耗竭， 收养细胞转移研究和流式细胞仪。同样在Hasty博士的指导下，我将 继续获得科学沟通和专业技能的培训 成为独立研究者。范德比尔特大学的科学环境 医疗中心非常适合帮助我实现研究免疫力的长期职业目标 系统和代谢疾病。有许多共享资源和核心设施 （有利的核心，流式细胞仪核心）和大量的协作机会 可用的。我以前的培训机会和科学技能为我提供了坚实的 肥胖，糖尿病，心血管疾病和非酒精性脂肪肝病的背景， 执行我建议的研究所必需的。因此，获得的知识和科学技能 在这项培训奖中，将有助于我为我的未来目标做好准备 学术界的研究科学家。 抽象的 随着代谢疾病的巨大增加，非酒精性脂肪肝病（NAFLD）是 在当今社会中逐渐普遍。 Nafld范围从肝脂肪变性到 肝硬化。非酒精性脂肪性肝炎（NASH）的特征是肝脂肪变性和混合 炎性细胞浸润，是纤维化进展的主要预测指标。最近，纳什 已被确定为心血管疾病的危险因素。众所周知 免疫细胞是炎症和纤维化的关键因素。虽然很多关注 放在库普弗细胞在NAFLD中的作用上，对 淋巴细胞的亚群及其对NAFLD的贡献。在肥胖条件下，CD8+ 已经发现T细胞调节脂肪组织中的巨噬细胞浸润。我们的初步 数据是第一个证明高脂血症诱导肝CD8+的早期浸润的数据 表达独特的Th2和细胞毒性表型的T细胞。这种肝淋巴细胞浸润 与肝炎症单核细胞和纤维纤维标记的增加有关。 但是，这些免疫细胞在纳什中的独特作用尚不清楚。因此，具体目的 该项目的是：1）确定在此期间识别肝CD8+ T细胞种群的表型 从脂肪变性到纳什的过渡； 2）在体内确定CD8+ T细胞的程度 影响纳什的发展； 3）在体内确定IL-10影响的程度 从肝脂肪变性到纳什的过渡。我们的假设是1）早期浸润CD8+ T细胞 表达细胞毒性和Th2表型，该表型驱动募集和纤维纤维 巨噬细胞中的表型； 2）CD8+ T细胞的耗竭将减少募集和 巨噬细胞的纤维化表型；而添加CD8+ T细胞将增加 在肝脂肪变性条件下巨噬细胞的纤维化表型； 3）耗尽 IL-10将降低NAFLD下肝巨噬细胞中的成能力表型 状况。从该提案中获得的数据有望为 预防和治疗纳什的治疗靶标的潜在发展 降低与这些疾病有关的医疗费用。