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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要候选人我的职业目标是在学术界指导一个成功的实验室，将细胞、动物和临床研究，以解决先天免疫系统对肥胖和肥胖的影响相关的代谢紊乱和营养物质对免疫细胞功能的影响。我是申请指导职业发展奖，因为它提供了绝佳的机会转型为独立调查员。目前我是博士后实习生。艾莉莎·哈斯蒂 (Alyssa Hasty) 的实验室，在那里我能够提高我的分子技术和获得使用免疫细胞以及肥胖和高脂血症动物模型的经验。我已经能够建立自己的独立研究项目，旨在研究肝脏的作用 CD8+ T 细胞在非酒精性脂肪肝疾病发展中的作用。多项研究技能将根据本提案获得，包括RNA测序、抗体去除、过继细胞转移研究和流式细胞术。同样在Hasty博士的指导下，我会继续获得科学传播和专业技能方面的培训，这是必要的成为一名独立调查员。范德比尔特大学的科研环境医疗中心非常适合帮助我实现研究免疫的长期职业目标系统和代谢疾病。拥有众多共享资源和核心设施（VANTAGE核心、流式细胞术核心）和大量的合作机会可用的。我之前的培训机会和科学技能为我提供了坚实的基础肥胖、糖尿病、心血管疾病和非酒精性脂肪肝疾病背景，执行我提议的研究所必需的。因此，获得的知识和科学技能在这次培训期间，奖励将帮助我为成为独立的未来目标做好准备学术界的研究科学家。抽象的随着代谢性疾病的大量增加，非酒精性脂肪性肝病（NAFLD）在当今社会逐渐变得普遍。 NAFLD 范围从肝脂肪变性到肝硬化。非酒精性脂肪性肝炎（NASH）的特点是肝脂肪变性和混合性脂肪变性。炎症细胞浸润，是纤维化进展的主要预测因子。最近，NASH 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。虽然受到了很多关注人们对库普弗细胞在 NAFLD 中的作用的关注有限淋巴细胞亚群及其对 NAFLD 的贡献。肥胖条件下，CD8+ 人们发现 T 细胞可以调节脂肪组织中的巨噬细胞浸润。我们的初步数据首次证明高脂血症会诱导肝脏 CD8+ 早期浸润表达独特 Th2 和细胞毒性表型的 T 细胞。这种肝淋巴细胞浸润与肝脏炎症单核细胞和纤维化标志物的增加相关。然而，这些免疫细胞在 NASH 中的独特作用尚不清楚。因此，具体目标该项目的目标是： 1) 鉴定肝 CD8+ T 细胞群在从脂肪变性转变为 NASH； 2) 确定体内 CD8+ T 细胞的程度影响 NASH 的发展； 3)确定体内IL-10影响的程度从肝脂肪变性到 NASH 的转变。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，驱动募集和促纤维化巨噬细胞的表型； 2) CD8+ T 细胞的耗竭将减少招募和巨噬细胞的促纤维化表型；而添加 CD8+ T 细胞会增加肝脂肪变性条件下巨噬细胞的促纤维化表型； 3）耗尽 IL-10 将降低 NAFLD 下肝巨噬细胞的促纤维化表型状况。从该提案中获得的数据预计将为预防和治疗 NASH 的潜在治疗靶点的开发，以及减少与这些疾病相关的医疗保健费用。