Complement Dependent Inflammation and Murine Heart Transplant Rejection

补体依赖性炎症和小鼠心脏移植排斥

• 批准号: 9915875
• 负责人: Nicholas Chun
• 金额: $ 19.03万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-03 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9915875
• 关键词: Allografting; Antibodies; Antigen Presentation; Antigens; Area; Award; B-Cell Activation; Biology; Cellular Immunity; Clinical; Communication; Complement; Complement Activation; Cross Presentation; Data; Environment; Eragrostis; Experimental Models; Faculty; Fostering; Functional disorder; Genetic; Graft Rejection; Grant; Heart Transplantation; Heart failure; Human; Human Resources; Image; Immune response; Immunity; Immunobiology; Immunoglobulin Class Switching; Immunology; Immunosuppression; Inflammation; Ischemia; Kidney Failure; Knock-out; Knowledge; Lead; Lectin Inhibitor; Link; Mannose Binding Lectin; Manuscripts; Mature B-Lymphocyte; Mediating; Mediator of activation protein; Mentors; Modeling; Mus; Nephrology; Organ; Organ Donor; Outcome; Pathogenicity; Patients; Pharmacology; Reperfusion Injury; Reperfusion Therapy; Research; Research Personnel; Resistance; Scientist; Statistical Data Interpretation; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Training; Training Activity; Translating; Transplant Recipients; Transplantation; Writing; activation-induced cytidine deaminase; adaptive immunity; allograft rejection; career development; effector T cell; exosome; graft failure; heart allograft; human disease; immunogenicity; improved; inhibitor/antagonist; insight; isoimmunity; large datasets; medical schools; mouse model; new therapeutic target; post-transplant; pre-clinical; skills; transplant model

Project Summary/Abstract Research Summary: Long-term post-transplant outcomes remain suboptimal, especially for recipients of deceased donor organs. Building upon previous studies, our preliminary data from a murine heart transplant model implicate peri-transplant complement-mediated ischemia reperfusion (IR) injury and inflammation as a central mediator of increased alloimmunity and late graft failure/dysfunction. In this project we will study the mechanisms and effects of complement activation on IR-associated inflammation (Aim 1) and the mechanisms linking increased IR-induced complement-dependent inflammation to late post-transplant allospecific immunity and outcomes (Aim 2). These aims will test our central hypothesis that IR-injury induced inflammation is dependent upon recipient mannose binding lectin-dependent complement activation, that inflammation induces greater recipient APC activation/donor antigen acquisition, and that these primed APCs then foster a stronger adaptive anti- donor T cell response leading to graft rejection. The specific findings have the potential to identify novel therapeutic targets that can be translated to human trials to improve transplant outcomes. Environment: Both the Icahn School of Medicine at Mount Sinai and Division of Nephrology are firmly committed to junior faculty career development. Dr. Peter Heeger (mentor) is an established expert in the field of complement immunology and transplant research with a strong record of developing junior faculty into independent researchers. Candidate Training: The primary objective of this application is to support Dr. Nicholas Chun's career development into an independent researcher scientist in the field of complement immunobiology and human disease. Dr. Chun's proposed training activities are in four broad non-mutually exclusive areas: 1) Enhancement of fundamental knowledge (e.g. immunology, complement, and exosome biology); 2) Scientific Communication (e.g. manuscript/grant writing, presentation skills); 3) Practical skills (e.g. statistical analysis, large data set analysis, advanced imaging); 4) Managerial skills (e.g. lab finances, personnel administration). The general approaches and skills outlined during this award will form the basis for future research. !

项目概要/摘要 研究摘要：长期移植后结果仍然不理想，尤其是对于受者而言 已故捐赠器官。基于之前的研究，我们从小鼠心脏获得的初步数据 移植模型暗示移植周围补体介导的缺血再灌注（IR）损伤和 炎症是同种免疫增加和晚期移植失败/功能障碍的中心介质。在这个 该项目我们将研究补体激活对 IR 相关的机制和影响 炎症（目标 1）以及 IR 诱导的补体依赖性增加的相关机制 炎症对移植后晚期同种异体特异性免疫和结果的影响（目标 2）。这些目标将考验 我们的中心假设是IR损伤诱导的炎症依赖于受体甘露糖 结合凝集素依赖性补体激活，炎症诱导更大的受体 APC 激活/供体抗原获取，并且这些引发的 APC 然后培养更强的适应性抗- 供体 T 细胞反应导致移植物排斥。具体的发现有可能确定 可以转化为人体试验以改善移植结果的新治疗靶点。 环境：西奈山伊坎医学院和肾脏科都坚定地 致力于青年教师的职业发展。 Peter Heeger 博士（导师）是以下领域的知名专家 补体免疫学和移植研究领域，在培养初级人才方面拥有良好的记录 教师转变为独立研究人员。候选人培训：此应用程序的主要目标是 支持Nicholas Chun博士的职业发展，成为该领域的独立研究科学家 补体免疫生物学和人类疾病。 Chun博士提议的培训活动分为四项 广泛的非互斥领域：1）增强基础知识（例如免疫学， 补体和外泌体生物学）； 2) 科学传播（例如手稿/资助写作， 演讲技巧）； 3）实践技能（例如统计分析、大数据集分析、高级 成像）； 4) 管理技能（例如实验室财务、人事管理）。一般方法 该奖项中概述的技能和技能将构成未来研究的基础。 ！