Investigating the role of pharmacological preconditioning of organs from brain dead donors to improve the outcomes of kidney transplantation

拟议研究的医学背景及其重要性：器官移植每年挽救成千上万患者的生命。大多数类型的器官移植，包括肝、肾、胰腺、心脏、肺甚至肠移植，现在被认为是终末期器官衰竭患者的最终治疗方法。尽管医学专业人员和公众对移植的认识不断提高，但器官供应和需求之间仍然存在着巨大的鸿沟。预计这种情况将在未来十年恶化，使这种差距成为当今移植界面临的最大挑战之一。为了调和这种差异，研究人员一直在探索如何扩大“供体池”，以及如何修复或恢复以前认为不适合移植的器官。即使考虑到免疫因素和储存时间，与活体捐赠者相比，脑死亡捐赠者捐赠的肾脏的短期和长期结果也较差。这些器官功能下降的部分原因是在脑死亡过程中血液、氧气和营养供应的减少。这导致有毒代谢物的产生，当血液供应恢复时，导致严重的组织损伤。此外，免疫系统似乎过度活跃。我推测，对脑死亡捐赠者进行干预可以帮助保护器官免受损害。在这样做的过程中，我提出干预措施将使以前无法使用的器官可以移植，并减少急性和慢性器官衰竭的发生率。人们认识到，一个器官短期的血液供应不足（缺血）可以防止长期缺血造成的未来损害。这种保护的机制尚未完全描述，然而，缺氧诱导因子（HIF）及其调节的基因被认为是负责一些授予的保护。HIF通路是细胞对缺氧反应机制的一部分。HIF可以通过给药二甲基羟基甘氨酸（DMOG）诱导。迄今为止，还没有发表的科学研究调查了HIF通路在预防脑死亡后肾损伤和改善移植结果中的作用。项目目标及方法：拟开展实验，探讨HIF通路在脑死亡后肾损伤保护中的作用。我将使用我在学术临床研究期间开发的大鼠模型。我将使用DMOG激活并维持HIF通路。我将使用包括大鼠肾移植模型在内的技术，评估用这种药物治疗的脑死亡大鼠获得的肾脏。通过本研究，我旨在建立DMOG对脑死亡所致肾损伤的消除作用，提高我们对脑死亡所致肾损伤机制的认识。这样做，我的目标是保护肾脏不受脑死亡器官捐赠者的影响，提高所获得肾脏的质量，同时也挽救了以前无法使用的肾脏，从而使无法移植的肾脏可以移植。

Medical context of proposed research and its importance: Organ transplantation saves the lives of thousands of patients every year. Most types of organ transplantation including liver, kidney, pancreas, heart, lung and even bowel transplants are now recognised as definitive treatments for patients with end stage organ failure. Despite the increasing awareness of transplantation both amongst medical professionals and members of the general public, a significant gulf still exists between organ availability and need. This is predicted to worsen over the course of the next decade making this disparity one of the biggest challenges facing the transplant community today. In an attempt to reconcile this difference researchers have been exploring how the "donor pool" can be expanded and how organs previously considered unsuitable for transplantation can be repaired or resuscitated.Kidneys donated from brain dead donors have poorer short and long-term outcomes when compared to living donors, even when immunological factors and storage times are taken into consideration. Part of the reason for the poorer function of these organs is because of a reduction in the blood, oxygen and nutrient supply during the brain death process itself. This leads to toxic metabolite production which, when the blood supply is restored, results in dramatic tissue injury. In addition, the immune system appears to be overactive. I speculate that interventions made in the brain dead donor can help protect organs against damage. In doing so, I propose that interventions will make previously unusable organs transplantable, and also reduce the incidence of acute and chronic organ failure. It is recognised that a short period of deprivation of blood supply (ischaemia) to an organ can prevent against future damage from prolonged ischaemic periods. The mechanism for this protection has not been fully delineated, however, Hypoxia Inducible Factor (HIF) and the genes that it regulates have been suggested as being responsible for some of the conferred protection. The HIF pathway is part of the cellular response mechanism to oxygen deprivation. HIF can be pharmacologically induced by administering dimethyloxaylglycine (DMOG). To date no published scientific research has investigated the role of the HIF pathway in preventing kidney injury following brain death and improving the outcomes of transplantation. Goals of project and methods:I propose to carry out experiments to explore the role of the HIF pathway in protecting against kidney injury following brain death. I will use a rat model I have developed during my Academic Clinical Fellowship. I will activate and sustain the HIF pathway using DMOG. I will be assessing the kidneys procured from brain dead rats treated with this agent using techniques including a rat model of renal transplantation. By conducting this research I aim to establish the ability of DMOG to abrogate the kidney injury caused by brain death, and improve our understanding of the mechanisms of brain death induced kidney injury. In doing so, I aim to protect kidneys from brain dead organ donors, improving the quality of kidneys procured, but also salvaging previously unusable kidneys and thereby making the untransplantable transplantable.