NF-kB Inhibition of Lung Ischemia Repurfusion Injury

描述（由申请人提供）：缺血再灌注损伤（IRI）是许多临床情况下的主要问题，包括心肌梗死和中风。IRI也是器官移植中的主要问题，因为IRI是移植后原发性移植物衰竭和器官功能障碍的主要原因。越来越多的人认为，植入时IRI引起的移植物损伤是延迟性移植物功能障碍（也称为慢性排斥反应）的主要原因。肺移植（LTX）延长并改善了数千名终末期肺病患者的生命，但受到来自传统器官供体（脑死亡、通气患者，其器官在受控心脏骤停后被取回）的合适供体供应不足的严重限制。在移植的实体器官中，肺是急性移植物衰竭发生率最高的器官之一，也是晚期移植物衰竭发生率最高的器官。每年有数百名移植候选人在接受移植前死亡，另有数千人甚至因肺供体短缺而不被考虑。如果肺可以从无心跳供体（NHBDs）-猝死的受害者-在循环停止后的间隔中取出并安全移植，则可以消除移植肺的短缺，并且可以通过LTX延长或增强数千名终末期肺病患者的生命。使用从NHBD取出的肺进行移植也与IRI相关。任何减少肺IRI的治疗都具有相当大的临床意义;它可以改善常规LTX的短期和长期结果，并且可以促进NHBDs的LTX。此外，如果这种疗法能够减少其他器官的IRI，将在器官移植领域和其他临床医学领域产生深远的影响。由于我们对从NHBDs中取出的肺移植感兴趣，我们广泛研究了肺IRI，并将先天免疫系统的效应子途径作为IRI引起的炎症的重要贡献者。其中，越来越多的证据表明，普遍存在的转录因子核因子κ-B（NF-（B））的激活是移植和其他IRI模型中IRI的关键因素。I期STTR的目的是确定抑制NF-β B是否可以改善肺IRI。我们已经开始与TheraLogics（一家生物技术公司）合作，评估两种药物抑制NF-β B活化的有效性：NEMO结合肽，通过干扰IKK（与IKK（和IKK（）的相互作用阻断NF-β B活化;化合物A，一种IKK（）的低分子量抑制剂。TheraLogics拥有这两种NF-（B）强效抑制剂的独家许可。我们将在I期研究中使用这两种抑制剂。我们将选择最有效的抑制剂进行II期研究。如果这些I期研究成功，转化肺移植模型的II期研究将为肺移植、NHBDs肺移植的临床试验以及其他类型器官移植和其他IRI临床情况的研究铺平道路。公共卫生相关性： 缺血再灌注损伤（IRI）是许多临床情况中的主要问题，包括心肌梗死、中风和器官移植，其中IRI是原发性移植物衰竭的主要原因;它也是延迟性移植物功能障碍（也称为慢性排斥）的主要促成因素。由于普遍存在的转录因子核因子κ B（NF-（B））的激活与IRI和器官移植有关，本提案概述了确定抑制NF-κ B的影响的实验。（B激活，通过肺IRI和移植方面的大学专家与TheraLogics的合作，TheraLogics是一家拥有两种NF-（B：NEMO结合肽和IKK低分子量抑制剂（该化合物的许可证正在更新）。在I期，我们建议在已建立的移植所致肺IRI的体外和体内模型中评估两种药物，如果我们确定NF-β B抑制的益处，则在II期，我们建议确定最有效药物在临床相关存活肺移植模型中的功效。

DESCRIPTION (provided by applicant): Ischemia-reperfusion injury (IRI) is a major problem in many clinical scenarios, including myocardial infarction and stroke. IRI is also a major problem in organ transplantation, because IRI is the major cause of primary graft failure and organ dysfunction after transplant. Increasingly, graft injury due to IRI at the time of implantation is recognized as a major contributor to delayed graft dysfunction, also known as chronic rejection. Lung transplantation (LTX) has extended and improved the lives of thousands of patients with end-stage lung disease, but is severely constrained by an inadequate supply of suitable donors from conventional organ donors (brain-dead, ventilated patients whose organs are retrieved after controlled cardiac arrest). Among solid organs transplanted, lungs have one of the highest rates of acute graft failure, and the highest incidence of late graft failure. Hundreds of transplant candidates die every year before receiving transplants, and thousands of others are not even considered candidates because of the lung donor shortage. If lungs could be retrieved from non-heart-beating donors (NHBDs) - victims of sudden death - at intervals after circulatory arrest and transplanted safely, the shortage of lungs for transplant could be eliminated, and the lives of thousands more patients with end-stage lung disease could be extended or enhanced by LTX. Transplant using lungs retrieved from NHBDs is also associated with IRI. Any therapy to reduce lung IRI would have considerable clinical importance; it could improve both short- and long-term results of conventional LTX, and it could facilitate LTX from NHBDs. In addition, if this therapy could reduce IRI in other organs, it would have far-reaching implications in the field of organ transplantation and other areas of clinical medicine. Because of our interest in transplanting lungs retrieved from NHBDs, we have studied lung IRI extensively, and have implicated effector pathways of the innate immune system as important contributors to inflammation due to IRI. Among these, there is growing evidence from our group and others that activation of the ubiquitous transcription factor nuclear factor kappa-B (NF-(B) is a critical contributor to IRI in transplantation and other IRI models. The purpose of the Phase I STTR is to determine if inhibition of NF-(B can ameliorate lung IRI. We have initiated a collaboration with TheraLogics, a biotechnology company, to evaluate the effectiveness of two agents to inhibit activation of NF-(B: NEMO binding peptides that block NF-(B activation by interfering with the interaction of IKK( with IKK( and IKK(; and Compound A, a low molecular weight inhibitor of IKK(. TheraLogics has exclusive licenses for both of these potent inhibitors of NF-(B. We will use both inhibitors in Phase I studies. We will select the most efficacious inhibitor for Phase II studies. If these Phase I studies are successful, Phase II studies in translational lung transplant models will pave the way for clinical trials in lung transplantation, lung transplantation from NHBDs, and studies in other types of organ transplant and other clinical scenarios of IRI. PUBLIC HEALTH RELEVANCE: Ischemia-reperfusion injury (IRI) is a major problem in many clinical scenarios, including myocardial infarction, stroke, and organ transplantation, where IRI is the major cause of primary graft failure; it is also a major contributor to delayed graft dysfunction, also known as chronic rejection. Because activation of the ubiquitous transcription factor nuclear factor kappa-B (NF-(B) is implicated in IRI and organ transplantation, this proposal outlines experiments to determine the impact of inhibiting NF-(B activation, through collaboration of a university-based expert in lung IRI and transplantation, and TheraLogics, a biotechnology company with exclusive licenses for two potent inhibitors of NF-(B: a NEMO binding peptide and a low molecular weight inhibitor of IKK( (license for this compound is being renewed). In Phase I, we propose to evaluate both agents in established in vitro and in vivo models of lung IRI due to transplant, and if we determine a benefit of NF-(B inhibition, in Phase II we propose to determine efficacy of the most effective agent in clinically relevant survival lung transplant models.