Stabilization of gap/tight junctions to ameliorate brain death induced endothelial cell injury

 描述（由申请人提供）：移植是一种广泛接受且非常成功的终末期心脏病治疗方法。虽然成功率和存活率自近50年前成立以来一直稳步上升，主要是由于免疫抑制制度的改善，但人们越来越认识到，植入前与脑死亡，器官捐赠，采购和储存相关的因素极大地影响移植后的结果。临床数据表明，与来自尸体来源的心脏相比，来自活体供体的心脏的受体具有显著改善的结果。这些数据表明，脑死亡和冷藏引起的供体器官损伤易导致移植后结局较差。这些有害事件被认为引发器官损伤、内皮功能障碍和炎症，这些在植入和再灌注后进一步恶化，并且引发供体器官进行同种免疫识别。因此，尽量减少或关闭这些有害事件的策略可能会改善移植结果。冷保存极大地促进了尸体心脏移植的使用，但是，很明显，损伤发生在脑死亡的储存之前，以及在保存期和再灌注期。虽然已将代谢添加剂掺入保存溶液中以延长储存时间并提高器官活力，但未将添加剂掺入保存溶液中以最小化内皮损伤/活化。我们假设，脑死亡，冷保存，缺血再灌注损伤诱导细胞连接损伤，导致炎症，心脏损伤，再灌注后内皮功能障碍，并列入一个新的间隙和紧密连接稳定肽，ACT 1，将保持细胞连接在冷保存和减少移植损伤和免疫原性再灌注。

 DESCRIPTION (provided by applicant): Transplantation is a widely accepted and highly successful therapy for end-stage heart disease. While success rates and survival have risen steadily since its inception almost 50 years ago, due largely to improved immunosuppression regimes, there is a growing appreciate that factors associated with brain death, organ donation, procurement and storage, prior to implantation greatly effect outcomes post transplantation. Clinical data has demonstrated that recipients of hearts from living donors have significantly improved outcomes as compared to those from cadaveric sources. These data suggest that insults to the donor organ induced by brain death, and cold storage, predispose to poorer post transplantation outcomes. These injurious events are thought to initiate organ injury, endothelial dysfunction, and inflammation that are further exacerbated upon implantation and reperfusion, and that primes the donor organ for alloimmune recognition. Therefore strategies to minimize or switch off these injurious events are likely to improve graft outcomes. Cold preservation has greatly facilitated the use of cadaveric hearts for transplantation but, clearly, damage occurs prior to storage from brain death, and during both the preservation episode and the reperfusion phase. While metabolic additives have been incorporated into preservation solutions to prolong storage times and improve organ viability no additives have been incorporated into the preservation solutions to minimize endothelial injury/activation. We hypothesize that brain death, cold preservation, and ischemia reperfusion injury induces cell junction damage, which leads to inflammation, heart damage, and endothelial dysfunction upon reperfusion, and that inclusion of a novel gap and tight junction stabilizing peptide, ACT1, would preserve cell junctions during cold preservation and reduce graft damage and immunogenicity upon reperfusion.