Therapeutic strategies to improve function of high risk liver grafts

项目总结 这项建议提出了一项为期五年的研究职业发展计划，旨在科学地提高 扩大标准供者(ECD)供肝移植的存活率。候选人目前是一名 杜克大学外科学助理教授。应聘者有以前的研究和临床经验 在涉及常温机器灌流(NMP)的移植手术中，器官被安置在前 活体环境和生理条件下灌流营养和氧气。候选人现在将会 通过使用NMP为移植移植物提供新的治疗方法来推动这项技术的发展，并专注于他的研究 线粒体在移植物功能障碍中的作用。这位候选人已经组建了一个多元化的指导委员会 拥有移植手术、NMP、分子治疗学和线粒体生物学专业知识的研究人员。 拟议的培训和实验将为候选人提供先天免疫方面的综合技能， 线粒体生物学、移植手术和生物统计学，使他能够过渡到研究 作为一名外科医生兼科学家，独立致力于减少移植手术领域的器官短缺。 肝移植领域面临的主要障碍是供体器官的严重短缺。2018年， 美国进行了8000例肝移植手术，但另有1.3万名患者仍在等待名单上。 轮候名单上的病人死亡率极高，每年超过20%。一个战略，具有很好的 增加器官可获得性的可能性是使用扩展标准捐赠者(ECDs)。ECD名称 包括高龄捐赠者(≥60岁)、患有严重肝脏脂肪变性的捐赠者以及在此之后捐献的肝脏 心源性死亡。然而，ECD肝脏的广泛使用受到几个因素的限制，包括增加 移植物功能障碍、移植物衰竭和受体死亡的比率。这些糟糕的结果被归因于 ECD肝脏从缺血再灌注(I-R)损伤中恢复的能力降低。缺血再灌注损伤诱导线粒体 移植物功能障碍，导致细胞死亡。移植物中的死亡细胞释放出大量的分子。 统称为损伤相关分子模式(DAMP)，它们被已知激活 炎症和细胞死亡途径，导致移植物进一步损伤。我们假设减少损害 线粒体功能障碍和潮湿会提高供移植的ECD肝脏的存活率并减少 目前可供移植的肝脏短缺。NMP技术的使用提供了一个理想的平台 用于提供治疗药物以改善ECD移植物功能。该项目将采用NMP技术来交付 使用我们的新型捕湿法增强线粒体功能和清除有害湿气的治疗 薄膜。这项建议的目的是：1)确定线粒体功能增强对ECD的影响 肝移植，2)确定去湿对移植肝损伤和功能的影响。

PROJECT SUMMARY This proposal presents a five-year research career development program focused scientifically on improving the viability of liver grafts from extended criteria donors (ECD) for transplantation. The candidate is currently an Assistant Professor of Surgery at Duke University. The candidate has previous research and clinical experience in transplant surgery involving normothermic machine perfusion (NMP), whereby an organ is housed in an ex vivo environment and perfused with nutrients and oxygen under physiologic conditions. The candidate will now advance this technology by using NMP to deliver novel therapeutics to transplant grafts, and focus his research on mitochondrial contributions to graft dysfunction. The candidate has assembled a diverse mentoring committee of investigators with expertise in transplant surgery, NMP, molecular therapeutics, and mitochondrial biology. The proposed training and experiments will provide the candidate with a combined skillset in innate immunity, mitochondrial biology, transplant surgery, and biostatistics that will enable him transition to research independence as a surgeon-scientist dedicated to reducing the organ shortage in the field of transplant surgery. The primary obstacle facing the field of liver transplantation is the severe shortage of donor organs. In 2018, 8,000 liver transplants were performed in the United States, but another 13,000 patients remain on the waitlist. The mortality rate of patients on the waitlist is exceedingly high, at over 20% per year. One strategy with great potential to increase organ availability is utilization of extended criteria donors (ECDs). The ECD designation includes donors of advanced age (≥ 60 years), those with significant hepatic steatosis, and livers donated after cardiac death. However, widespread use of ECD livers has been limited by several factors, including increased rates of graft dysfunction, graft failure, and recipient death. These poor outcomes have been attributed to a reduced capacity of ECD livers to recover from ischemia-reperfusion (I-R) injury. I-R injury induces mitochondrial dysfunction in the graft that leads to cell death. The dying cells in the graft release a broad array of molecules known collectively as damage-associated molecular patterns (DAMPs), which are known to activate inflammatory and cell death pathways, leading to further graft injury. We hypothesize that reducing the damage caused by mitochondrial dysfunction and DAMPs will improve the viability of ECD livers for transplant and reduce the current shortage of livers available for transplantation. The use of NMP technology provides an ideal platform for delivering therapeutics to improve ECD graft function. This project will employ NMP technology to deliver therapeutics that enhance mitochondrial function and removing harmful DAMPs using our novel DAMP-capturing membrane. The aims of this proposal are: 1) determine the effects of enhanced mitochondrial function on ECD liver transplantation, 2) determine the effects of removing DAMPs on post-transplant graft injury and function.