Improving transplant organ survival through the mitigation of donor-derived mitochondrial damage-associated molecular patterns

通过减轻供体来源的线粒体损伤相关分子模式来提高移植器官的存活率

• 批准号: 10029329
• 负责人: Andrew Serghios Barbas
• 金额: $ 40.76万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-17 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10029329
• 关键词: Allografting; Animal Model; Blood Circulation; Brain Death; Cells; Clinical; Clinical Trials; Data; Development; Disease; Etiology; Foundations; Functional disorder; Goals; Graft Rejection; Graft Survival; Heart Transplantation; Human; Immune; Immune response; Infection; Inferior; Inflammation; Inflammatory; Inflammatory Response; Injury; Injury to Kidney; Intervention; Kidney; Knowledge; Life; Living Donors; Malignant Neoplasms; Mediating; Methods; Mission; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Organ; Organ Donor; Organ Survival; Organ Transplantation; Outcome; Pathway interactions; Pattern; Perfusion; Play; Process; Public Health; Rattus; Reactive Oxygen Species; Research; Risk; Role; Sampling; Savings; Serum; Signal Pathway; Signal Transduction; Solid; Sterility; Testing; Therapeutic Intervention; Therapeutic immunosuppression; Tissues; Transplantation; United States; United States National Institutes of Health; Waiting Lists; cytokine; ex vivo perfusion; experimental study; extracellular; formyl peptide; graft function; human tissue; immunogenicity; improved; innate immune pathways; innovation; intravenous injection; liver transplantation; mouse model; neutrophil; novel strategies; organ transplant rejection; post-transplant; preimplantation; preservation; response; success; targeted treatment; therapeutic development; transplant model

The need for transplantation vastly exceeds organ availability, and many of the over 30,000 solid organ transplants (grafts) performed in the United States annually will be lost within 5 years —primarily as a result of immune-mediated graft rejection. Thus, there is a critical need for improved approaches to reduce graft rejection and to expand the pool of usable organs. A novel strategy for reducing rejection and improving graft quality is to mitigate graft injury occurring prior to transplantation. The majority of transplant organs are from deceased donors, which have inferior outcomes when compared to organs from living donors. This difference is believed to be a result of increased graft injury and immunogenicity caused by inflammation resulting from brain death. The rationale for the proposed research is that identifying the specific cellular and molecular pathways that promote graft rejection in deceased organ donors will lead to the development of novel approaches to improve organ quality prior to transplant. It is now known that mitochondria released into the circulation after brain death are potent stimulators of sterile inflammation and promote graft dysfunction and rejection. The overall objectives of this proposal are to define the specific mitochondria-derived damage associated molecular patterns (mtDAMPs) that cause graft injury, and to develop methods to mitigate mtDAMP-induced inflammation in order to improve graft quality prior to transplantation. The central hypothesis is that the function and survival of transplanted organs can be improved by reducing graft inflammation and injury caused by circulating mitochondria in deceased donors. Guided by strong preliminary data, and using a combination of animal models and human tissues, the hypothesis will be tested through completion of three Specific Aims: 1) Identify the mtDAMPs responsible for increasing organ rejection; 2) Determine the effect of inhibiting mtDAMPs during machine perfusion on graft preservation and post-transplant graft function; and 3) Evaluate the ability of mtDAMP-targeting therapies to reduce human kidney injury during machine perfusion. The results obtained by completing the aims of this proposal will be significant because they will identify specific innate immune pathways responsible for inflammation in deceased organ donors and during ex vivo perfusion. This knowledge will accelerate the development of candidate therapies for abrogating these responses and mitigating graft injury prior to transplant, thus expanding organ utilization and improving organ quality. Treating grafts pre-implantation as a strategy to reduce immune responses following transplant and reduce rates of rejection, or to improve organ quality ex vivo, is innovative, and represents a paradigm shift for strategies aimed at improving transplant outcomes. The knowledge gained though completion of this project will provide a foundation to support subsequent studies, including human clinical trials, with the long-term goal of developing interventions that increase the clinical success of organ transplantation by improving donor organ quality.

对移植的需求大大超过了器官的可用性，在30，000多个实体器官中， 每年在美国进行的移植（移植）将在5年内丢失-主要是由于 免疫介导的移植排斥反应。因此，迫切需要改进的方法来减少移植物的移植。 排斥反应和扩大可用器官库。减少排斥反应和改善移植物的新策略 质量是减轻移植前发生的移植物损伤。大多数移植器官来自 与活体捐赠者的器官相比，已故捐赠者的结果较差。这种差异 被认为是由于移植物损伤和免疫原性增加的结果， 脑死亡这项研究的基本原理是，确定特定的细胞和分子 促进已故器官供体移植排斥反应的途径将导致新的 在移植前改善器官质量的方法。现在我们知道，线粒体释放到 脑死亡后的血液循环是无菌炎症的有力刺激物，并促进移植物功能障碍， 排斥反应本提案的总体目标是界定具体的海洋衍生损害， 相关的分子模式（mtDAMP），导致移植物损伤，并开发方法，以减轻 mtDAMP诱导的炎症，以便在移植前改善移植物质量。核心假设 移植器官的功能和存活可以通过减少移植物炎症来改善， 死亡捐赠者的循环线粒体造成的损伤。在强有力的初步数据的指导下， 动物模型和人体组织的组合，该假设将通过完成三个 具体目的：1）确定负责增加器官排斥反应的mtDAMP; 2）确定 在机器灌注期间抑制mtDAMP对移植物保存和移植后移植物功能的影响;以及3） 评价mtDAMP靶向治疗在机器灌注期间减少人肾损伤的能力。 通过完成本提案的目标所取得的成果将是重要的，因为它们将确定 负责死亡器官供体和离体过程中炎症的特异性先天免疫途径 灌注。这些知识将加速候选疗法的发展，以消除这些疾病。 在移植前减轻移植物损伤，从而扩大器官利用并改善器官功能。 质量.移植前处理移植物作为减少移植后免疫反应的策略， 降低排斥率，或改善离体器官质量，是创新的，并代表了一个范式转变， 旨在改善移植结果的策略。通过完成本项目获得的知识 将为支持后续研究提供基础，包括人类临床试验，长期目标是 开发干预措施，通过改善供体， 器官质量