NF-kB Inhibition of Lung Ischemia Repurfusion Injury

NF-kB对肺缺血再灌注损伤的抑制作用

• 批准号: 7750074
• 负责人: Patrick Michael Flood
• 金额: $ 25.56万
• 依托单位: THERALOGICS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7750074
• 关键词: Acute; Affect; Allografting; Animals; Area; Binding; Biotechnology; Blood Circulation; Brain Death; Bronchiolitis Obliterans; Caring; Cell Culture Techniques; Cells; Cessation of life; Chronic; Clinical; Clinical Medicine; Clinical Trials; Collaborations; Craniocerebral Trauma; Data; Edema; Effectiveness; Endothelial Cells; Environmental air flow; Epithelial Cells; Family suidae; Functional disorder; Heart; Heart Arrest; Human; Immune system; In Vitro; Incidence; Inflammation; Inflammation Mediators; Injury; International; Interruption; Lead; Licensing; Life; Lung; Lung Transplantation; Lung diseases; Marketing; Mediator of activation protein; Modeling; Molecular Weight; Myocardial Infarction; NF-kappa B; Organ; Organ Donor; Organ Transplantation; Outcome; Pathway interactions; Patients; Peptides; Perfusion; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phosphotransferases; Rattus; Reperfusion Injury; Reperfusion Therapy; Respiratory physiology; Retrieval; Risk Factors; Role; Simulate; Small Business Technology Transfer Research; Solid; Staging; Stroke; Structure of parenchyma of lung; Sudden Death; Survival Rate; Syndrome; Testing; Time; Transplant Recipients; Transplant-Related Disorder; Transplantation; Universities; Warm Ischemia; base; clinical efficacy; clinically relevant; cost; ex vivo perfusion; experience; fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; graft failure; hazard; implantation; improved; in vivo Model; inhibitor/antagonist; interest; lung development; lung ischemia; pre-clinical; prevent; public health relevance; research study; restoration; success; transcription factor

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.

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也是器官移植中的一个主要问题，因为IRI是移植后原发移植物衰竭和器官功能障碍的主要原因。越来越多地，植入时IRI引起的移植物损伤被认为是移植物迟发性功能障碍的主要原因，也称为慢性排斥反应。肺移植(LTX)延长和改善了数千名终末期肺部疾病患者的生命，但受到传统器官捐赠者(脑死亡、呼吸机患者，其器官在受控心脏骤停后被取回)合适供体供应不足的严重制约。在移植的实体器官中，肺是急性移植物失败率最高的器官之一，也是晚期移植物失败率最高的。每年有数百名移植候选人在接受移植前死亡，还有数千人甚至因为肺捐赠者短缺而不被考虑。如果能够在循环停止后每隔一段时间从非心脏跳动供者(NHBD)--猝死的受害者那里取出肺并安全地移植，就可以消除供移植的肺短缺的问题，并通过LTX延长或提高数千名终末期肺部疾病患者的生命。使用从NHBD中取出的肺进行移植也与IRI有关。任何减少肺IRI的治疗方法都将具有相当重要的临床意义；它可以改善常规LTX的短期和长期效果，并且它可以促进NHBD的LTX。此外，如果这种疗法能够减少其他器官的IRI，将对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NHBD中提取的肺移植感兴趣，我们对肺IRI进行了广泛的研究，并发现先天免疫系统的效应通路是IRI引起炎症的重要因素。其中，越来越多的证据表明，在移植和其他IRI模型中，普遍存在的转录因子核因子kappa-B(NF-(B))的激活是IRI的关键因素。第一阶段试验的目的是确定抑制核因子-(B)是否可以改善肺IRI。我们已经开始与生物技术公司TheraLogics合作，评估两种药物抑制NF-(B：NEMO结合肽，通过干扰IKK(和IKK(；)的相互作用来阻断NF-(B)的激活)的有效性，以及化合物A，一种IKK(。TheraLogics拥有这两种有效的核因子-(B)抑制剂的独家许可证，我们将在第一阶段研究中使用这两种抑制剂。我们将为第二阶段的研究选择最有效的抑制剂。如果这些第一阶段的研究成功，转化型肺移植模型的第二阶段研究将为肺移植的临床试验、从NHBD进行的肺移植以及其他类型的器官移植和其他IRI的临床方案的研究铺平道路。公共卫生相关性： 缺血再灌注损伤(IRI)是许多临床情况下的主要问题，包括心肌梗死、中风和器官移植，IRI是移植物原发衰竭的主要原因，也是迟发性移植物功能障碍的主要因素，也称为慢性排斥反应。由于普遍存在的转录因子核因子kappaB(B)的激活与IRI和器官移植有关，因此本建议概述了通过与一所大学的肺IRI和移植专家以及TheraLogics公司的合作，通过实验来确定抑制NF-(B)激活的影响，TheraLogics是一家生物技术公司，拥有两种有效的NF-B抑制剂的独家许可证(B：一种NEMO结合多肽和一种IKK的低分子抑制物)(该化合物的许可证正在续签中)。在第一阶段，我们建议在建立的体外和体内移植肺IRI模型中评估这两种药物，如果我们确定了核因子-B抑制的益处，在第二阶段，我们建议确定最有效的药物在临床相关的存活肺移植模型中的有效性。