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: 9199593
• 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/9199593
• 关键词: Academia; Academic Medical Centers; Address; Adipose tissue; Adoptive Cell Transfers; Animal Experimentation; Animal Model; Antibodies; Attention; Award; Benign; CD8-Positive T-Lymphocytes; Carcinoma; Cardiovascular Diseases; Cell model; 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; IL10 gene; Immune; Immune system; Incidence; Infiltration; Inflammation; Inflammatory; Innate Immune System; Insulin Resistance; Interleukin-10; K-Series Research Career Programs; Knowledge; Kupffer Cells; Laboratories; Lead; Liver; Liver Fibrosis; 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; Recruitment Activity; Research; Research Personnel; Research Project Grants; Resource Sharing; Role; Scientist; Societies; Solid; Techniques; Testing; Tissue Inhibitor of Metalloproteinase-1; Training; Triglycerides; Wound Healing; base; cardiovascular risk factor; career; cytotoxic; disorder prevention; effective therapy; experience; in vivo; insight; liver injury; macrophage; monocyte; mouse model; non-alcoholic fatty liver; nonalcoholic steatohepatitis; prevent; response; skills; therapeutic development; therapeutic target; training opportunity; transcriptome sequencing

DESCRIPTION (provided by applicant): 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. (End of Abstract)

描述（由申请人提供）：我的职业目标是在学术界指导一个成功的实验室，结合细胞、动物和临床研究来解决先天免疫系统对肥胖和相关代谢紊乱的影响，以及营养物质对免疫的影响细胞功能。我正在申请指导职业发展奖，因为它提供了转变为独立调查员的绝佳机会。目前，我是 Alyssa Hasty 博士实验室的博士后实习生，在那里我能够提高我的分子技术，并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 CD8+ T 细胞在非酒精性脂肪肝疾病发展中的作用。根据本提案，将获得许多研究技能，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，我将继续接受科学方面的培训。 沟通和专业技能是成为独立调查员所必需的。范德比尔特大学医学中心的科学环境非常适合帮助我实现研究免疫系统和代谢疾病的长期职业目标。有大量共享资源和核心设施（VANTAGE 核心、流式细胞术核心）以及大量可用的合作机会。我之前的培训机会和科学技能为我提供了肥胖、糖尿病、心血管疾病和非酒精性脂肪肝疾病方面的扎实背景，这是执行我拟议的研究所必需的。因此，在这次培训中获得的知识和科学技能将帮助我为成为学术界独立研究科学家的未来目标做好准备。摘要 随着代谢性疾病的大量增加，非酒精性脂肪性肝病（NAFLD）在当今社会日益常见。 NAFLD 的范围从肝脂肪变性到肝硬化。非酒精性脂肪性肝炎 (NASH) 的特征是肝脏脂肪变性和混合炎症细胞浸润，是纤维化进展的主要预测因素。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。虽然库普弗细胞在 NAFLD 中的作用受到了很多关注，但对淋巴细胞亚群及其对 NAFLD 的贡献的关注却很有限。在肥胖条件下，CD8+ T 细胞被发现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表达独特 Th2 和细胞毒性表型的肝脏 CD8+ T 细胞的早期浸润。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，该项目的具体目标是： 1) 鉴定从脂肪变性到 NASH 转变过程中肝脏 CD8+ T 细胞群的表型； 2) 确定体内 CD8+ T 细胞对 NASH 发展的影响程度； 3)确定体内IL-10对肝脂肪变性向NASH转变的影响程度。我们的假设是 1) 早期浸润的 CD8+ T 细胞表达细胞毒性和 Th2 表型，从而驱动巨噬细胞的募集和促纤维化表型； 2) CD8+ T细胞的耗竭将减少巨噬细胞的募集和促纤维化表型；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) IL-10的消耗将降低NAFLD条件下肝巨噬细胞中的促纤维化表型。从该提案中获得的数据预计将为预防和治疗 NASH 的治疗靶点的潜在开发提供重要见解，并降低与这些疾病相关的医疗保健成本。 （摘要完）