Immune mechanisms of ischemic hepatocyte injury in the steatotic liver

脂肪肝缺血性肝细胞损伤的免疫机制

• 批准号: 8550039
• 负责人: Nitika Arora Gupta
• 金额: $ 15.07万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-25 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8550039
• 关键词: Adoptive Transfer; Antibodies; Apoptosis; Area; Autoimmunity; Autophagocytosis; Behavior; Biliary; CD4 Positive T Lymphocytes; CXCL10 gene; Cell Adhesion Molecules; Cell Death; Cell physiology; Cells; Cellular biology; Cessation of life; Chemicals; Childhood; Clinical; Coculture Techniques; Comorbidity; Critical Pathways; Data; Diet; Disease model; Environment; Enzymes; Excision; Fatty Liver; Fatty acid glycerol esters; Foundations; Future; Genes; Goals; Health Care Costs; Heart failure; Hepatectomy; Hepatic; Hepatitis C; Hepatobiliary; Hepatocyte; Hepatology; Histology; ICAM1 gene; Immune; Immune response; Immune system; In Situ Nick-End Labeling; Incidence; Inflammatory; Injury; Integrins; Intervention; Intrinsic factor; Investigation; K-Series Research Career Programs; Life; Link; Lipids; Liver; Liver Dysfunction; Liver diseases; Mediating; Memory; Mentors; Mentorship; Modeling; Molecular; Morbidity - disease rate; Morphology; Mus; Necrosis; Obesity; Operative Surgical Procedures; Organ; Organ Procurements; Outcome; Pathway interactions; Patients; Phenotype; Play; Production; Recovery; Reperfusion Injury; Reperfusion Therapy; Research; Research Personnel; Research Proposals; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Role; Sepsis; Shapes; Shock; Signal Transduction; Signaling Molecule; Small Interfering RNA; Splenic Tissue; Staining method; Stains; Structure; Surface; Surgical Models; T-Cell Activation; T-Lymphocyte; Therapeutic Intervention; Time; Training; Transplantation; Up-Regulation; Western Blotting; adaptive immunity; base; career; cellular imaging; chemokine; cytokine; feeding; immune function; in vitro Model; indexing; inhibitor/antagonist; injured; insight; liver injury; liver ischemia; mortality; non-alcoholic fatty liver; novel; research study; response; therapeutic target; trafficking

DESCRIPTION (provided by applicant): The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing, in concert with the general rise in obesity. A fatty liver is substantially more susceptible to ischemic injury as compared to a normal liver, responding with increased cell death and commensurate liver dysfunction. Ischemic injury is commonly encountered clinically, influencing recovery from hepatobiliary surgery, systemic shock, and transplantation, and thus leads to increased morbidity and mortality in patients with NAFLD. The presence of steatosis is also detrimental in the setting of organ procurement as it increases the number of non-utilizable organs and limits the donor pool. Though the exact mechanism for the increased vulnerability of a steatotic liver to ischemic insults is not known, there is evidence to show that CD4+ T cells are centrally involved. The overall goal of this project is to define the role of the adaptive immune system, and in particular T cells, in mediating post ischemic injury of a steatotic liver. Utilizing a surgical model of partial hepatic ischemia, key molecules and pathways involved in T cell and steatotic hepatocyte crosstalk will be investigated. Preliminary data have shown that T cell activation in the setting of steatotic hepatocytes is distinct from tha seen with normal hepatocytes. The specific aims of this proposal will examine the mechanistic links between T cells (activation, repertoire, effector phenotype, and trafficking), and steatotic hepatocyte cell death following ischemia reperfusion injury, and in particular, identify translatable targets for therapeutic intervention. The applicant for this mentored career development award is a pediatric hepatologist with a proven track record of commitment to research in liver disease. With a unique niche, an excellent mentorship structure and a supportive environment, this research proposal will provide the necessary training and opportunity for the applicant to develop into an independent researcher and make a significant contribution to the field of hepatology.

描述(申请人提供)：非酒精性脂肪性肝病(NAFLD)的发病率正在增加，与肥胖症的普遍上升相一致。与正常肝脏相比，脂肪肝更容易受到缺血性损伤，其反应是细胞死亡增加和相应的肝功能障碍。缺血性损伤在临床上常见，影响肝胆手术、全身性休克和移植的恢复，从而导致NAFLD患者的发病率和死亡率增加。脂肪变性的存在在器官采购方面也是有害的，因为它增加了不能利用的器官的数量，限制了捐赠者的来源。尽管脂肪变性肝脏对缺血损伤易感性增加的确切机制尚不清楚，但有证据表明 CD_4~+T细胞起着中心作用。该项目的总体目标是确定适应性免疫系统，特别是T细胞在脂肪变性肝脏缺血后损伤中的作用。利用部分肝缺血的外科模型，研究T细胞和脂肪变性肝细胞串扰的关键分子和途径。初步数据显示，脂肪变性肝细胞的T细胞活化与正常肝细胞不同。这项建议的具体目的将研究T细胞(激活、谱系、效应表型和运输)与缺血再灌注损伤后脂肪变性肝细胞死亡之间的机制联系，特别是确定治疗干预的可翻译靶点。这项指导职业发展奖的申请者是一位儿科肝病专家，在肝病研究方面有良好的记录。凭借独特的利基市场、优秀的导师结构和支持性的环境，这项研究提案将为申请者提供必要的培训和机会，使其发展成为一名独立的研究人员，并为肝病领域做出重大贡献。