Preservation of DCD Allograft Integrity for Liver Transplantation

项目总结 肝移植是治疗终末期肝病的唯一权威疗法。一大批肝脏捐赠者 来自心脏死亡(DCD)后的捐赠。DCD捐赠者面临的挑战是长期的温暖 缺血可导致严重的肝功能障碍，从而导致早期同种异体移植的发展。 受者的功能障碍(EAD)或甚至原发无功能(PNF)。一种治疗药物的开发 保持DCD肝脏供体的完整性在减少EAD/PNP方面具有重要的治疗价值 在肝脏移植后。在此之前，我们认为MG53是细胞膜修复的重要成分。在……里面 在这项提议中，我们提出了有希望的数据来支持肌肉-肝脏通过MG53串扰的科学假设 作为一种肌动蛋白，是肝细胞保护的重要组成部分。而肝脏不表达 内源性MG53蛋白，MG53可以从循环转移到靶细胞损伤的肝细胞在 肝损伤急性期。生化和活细胞成像研究表明，MG53可以与 MLKL可保持肝细胞的完整性。使用常温体外肝脏灌流(NEVLP)平台， 我们发现，灌流液中存在重组人MG53(RhMG53)蛋白可以 提高肝脏捐赠者的诚信。因此，我们设想rhMG53可以作为一种新型的生物试剂来治疗 提高肝移植期间供体器官的保存和功能。本项目中设计的研究 重点阐明肌源性MG53在肝脏保护中的生理作用，并阐明 MG53介导的损伤肝细胞MLKL信号调控的潜在机制(目标1)； 应用重组人MG53维持DCD供者肝脏完整性的安全性和有效性 NEVLP和改善动物模型中的肝移植结果(目标2)。

PROJECT SUMMARY Liver transplantation is the only definitive therapy for end-stage liver disease. A significant pool of liver donors comes from donation after cardiac death (DCD). The challenge with DCD donors is the prolonged warm ischemia that can result in significant liver dysfunction, thus leading to the development of early allograft dysfunction (EAD) or even primary non-function (PNF) in the recipient. Development of a therapeutic agent to preserve DCD liver donor integrity would have significant therapeutic value in reducing EAD/PNP during or after a liver transplant. Previously we identified MG53 as an essential component of cell membrane repair. In this proposal, we present promising data to support the scientific premise that muscle-liver crosstalk via MG53 as a myokine constitutes an integral part of hepatocellular protection. While the liver does not express endogenous MG53 protein, MG53 can translocate from circulation to target injured hepatocytes during the acute phase of hepatic injury. Biochemical and live cell imaging studies revealed that MG53 can interact with MLKL to preserve hepatocellular integrity. Using the normothermic ex-vivo liver perfusion (NEVLP) platform, we found that the presence of recombinant human MG53 (rhMG53) protein in the perfusion solution could improve liver donor integrity. We thus envision that rhMG53 can function as a novel biological reagent to improve donor organ preservation and function during liver transplantation. Studies designed in this project focus on defining the physiological role of muscle-derived MG53 in hepatoprotection and elucidating the underlying mechanisms of MG53-mediated control of MLKL signaling in injured hepatocytes (Aim 1); and establishing the safety and efficacy of using rhMG53 to preserve the integrity of DCD liver donors during NEVLP and to improve liver transplant outcomes in animal models (Aim 2).