The role of ischaemia reperfusion injury and mitochondrial dysfunction in the development of chronic allograft vasculopathy

移植是挽救生命的治疗终末期器官衰竭，包括心脏，肾脏和肝脏。近几十年来，移植结果有了显著改善，但慢性排斥反应仍然是当今实体器官移植面临的主要挑战之一。免疫系统对移植器官的识别是这一过程的核心。然而，越来越多的证据表明，在移植时，被称为缺血再灌注损伤（IRI）的含氧血流的中断和随后的恢复不仅会导致初始器官损伤，而且还会加剧慢性排斥反应。IRI加重慢性排斥反应的确切机制仍有待阐明，目前还没有确定的治疗方法来改善IRI。线粒体是细胞内的细胞器，对细胞内的能量产生至关重要，并在介导IRI的损伤作用中起关键作用。最近，已经开发出了特异性的尿道靶向疗法，这些疗法已被证明可以减轻IRI。这些已经在广泛的动物模型和人体临床试验中证明是安全有效的。因此，它们在移植中的应用非常有吸引力。该项目将使用成熟的小鼠心脏移植慢性排斥模型来研究线粒体功能障碍和IRI与免疫系统相互作用加剧慢性排斥反应的机制。此外，还将确定靶向治疗在改善移植后慢性排斥反应方面的疗效。我们的目的是表明IRI对移植后的长期移植结果有显著的不利影响，并研究IRI有害影响的潜在机制。此外，我们建议表明，已经证明在非移植环境中对人类安全的肾脏靶向治疗可以改善移植后的长期移植结果。希望本研究将有助于及时有效地将这些疗法引入临床实践。

Transplantation is the life-saving treatment for end-stage organ failure, including heart, kidney and liver. Transplantation outcomes have improved significantly in recent decades, but chronic rejection remains one of the major challenges facing solid organ transplantation today. Recognition of the transplanted organ by the immune system as foreign is central to this process. There is, however, increasing evidence that the interruption and subsequent restoration of oxygenated blood flow to the organ at the time of transplantation, known as ischaemia reperfusion injury (IRI), can not only result in initial organ damage but can also exacerbate chronic rejection. The exact mechanism by which IRI exacerbates chronic rejection is still to be elucidated and there are no established treatments to ameliorate IRI.Mitochondria are intracellular organelles that are critical for energy production within cells and play a key role in mediating the damaging effects of IRI. Recently, specific mitochondrial-targeted therapies have been developed that have been shown to attenuate IRI. These have already been shown to be safe and effective in extensive animal models and human clinical trials. Their application to transplantation is therefore, very appealing. This project will use well-established mouse heart transplant models of chronic rejection to examine the mechanisms by which mitochondrial dysfunction and IRI interact with the immune system to exacerbate chronic rejection. Furthermore, the efficacy of mitochondria-targeted therapies in ameliorating chronic rejection after transplantation will be established. We aim to show that IRI has a significant detrimental impact on long term graft outcomes after transplantation, and to examine the underlying mechanisms responsible for the deleterious effects of IRI. Furthermore, we propose to show that mitochondrial-targeted therapies, which have already been shown to be safe in humans in non-transplant settings, can improve long term graft outcomes after transplantation. It is hoped that this study will facilitate the timely and efficient introduction of these therapies into clinical practice.