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Novel preservation fluid for organ transplantation

新型器官移植保存液

基本信息

批准号：
6691852
负责人：
JON G MABLEY
金额：
$ 18.35万
依托单位：
INOTEK PHARMACEUTICALS CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-01 至 2004-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Nitric oxide and peroxynitrite are reactive, short-lived species that are important mediators of various forms of hypoxia - reperfusion injury. One of the dow5nstream pathways of peroxynitrite-mediated organ injury is related to activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS). Based on in vitro and in vivo preliminary data, the applicants propose that the PARS pathway may play a role in the pathogenesis of the reperfusion injury associated with the transplantation of hypoxic organs, and propose studies to directly test the hypothesis that PARP inhibition supplementation in the organ storage fluid is able to improve the function of the transplanted organ. The first aim of the current project is to establish time course of PARS activation and associated organ dysfunction in an experimental kidney transplantation model, and to correlate these alterations with reactive nitrogen species formation in the organ. Reactive nitrogen species formation and PARS activation will be investigated using immunohistochemistry, and organ function will be investigated using conventional techniques. The second aim of the project is to perform direct studies into the role of PARS-related transplantation-induced kidney dysfunction. We will compare traditional organ preservation fluids with ones spiked with a novel potent PARS inhibitor, followed by evaluation of changes in the kidney function associated with transplantation. We will also evaluate the effect of treatment of the recipient with PARS inhibitor. Our studies will provide novel mechanistic information on ischemic storage and transplantation-related renal dysfunction which will be utilized for the future design and commercial development of novel organ preservation fluids.

描述（由申请人提供）：一氧化氮和过氧亚硝酸盐是反应性的，短暂的物种，是各种形式的缺氧-再灌注损伤的重要介质。过氧亚硝基阴离子介导的器官损伤的下游途径之一与核酶聚（ADP-核糖）合成酶（PARS）的激活有关。基于体外和体内初步数据，申请人提出PARS途径可能在与缺氧器官移植相关的再灌注损伤的发病机制中发挥作用，并提出研究直接检验器官储存液中补充PARP抑制剂的假设能够改善移植器官的功能。本项目的第一个目的是建立PARS激活的时间过程和相关的器官功能障碍的实验性肾移植模型，并将这些变化与活性氮形成的器官。将使用免疫组织化学研究活性氮物质形成和PARS活化，并使用常规技术研究器官功能。该项目的第二个目的是对PARS相关移植诱导的肾功能障碍的作用进行直接研究。我们将比较传统的器官保存液与一种新的强效PARS抑制剂，然后评估与移植相关的肾功能变化。我们还将评估用PARS抑制剂治疗受体的效果。我们的研究将提供新的机制信息缺血存储和移植相关的肾功能不全，将用于未来的设计和商业开发的新型器官保存液。