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. !

项目总结/摘要 研究总结：移植后长期结局仍不理想，尤其是对受者而言 死者捐赠器官基于先前的研究，我们从小鼠心脏获得的初步数据 移植模型涉及移植周围补体介导缺血再灌注（IR）损伤， 炎症作为增加的同种异体免疫和晚期移植物衰竭/功能障碍的中心介质。在这 本项目将研究补体激活对IR相关的免疫反应的机制和作用。 炎症（目的1）和IR诱导的补体依赖性增加的机制 炎症对移植后晚期同种异体免疫和结果的影响（目的2）。这些目标将检验 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，然后这些引发的APC培养更强的适应性抗- 供体T细胞反应导致移植物排斥。具体的调查结果有可能确定 新的治疗靶点可以转化为人体试验，以改善移植结果。 环境：西奈山伊坎医学院和肾脏科都坚定地 致力于初级教师的职业发展。Peter Heeger博士（导师）是一位公认的专家， 在补体免疫学和移植研究领域， 成为独立的研究人员。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员科学家 补体免疫生物学和人类疾病的关系秦博士建议的培训活动分为四个部分 广泛的非相互排斥的领域：1）加强基础知识（如免疫学， 补体和外泌体生物学）; 2）科学交流（例如手稿/资助写作， 3）实践技能（如统计分析、大型数据集分析、高级 4）管理技能（如实验室财务、人事管理）。一般方法 和技能概述在这个奖项将形成未来的研究基础。 !