Mitochondrial regulation of the NLRP3 inflammasome in myocardial ischemia-reperfusion injury and heart transplantation

项目摘要 心脏移植（HTx）是终末期心力衰竭的唯一确定性治疗方法， 内科或外科治疗和干预失败。尽管取得了进展， HTx患者的管理仍然迫切需要优化术后的长期结局， HTx。非裔美国人HTx接受者的累积死亡风险特别高。而 非洲裔美国人HTx接受者结果的种族差异是有据可查的， 这一差异的基础尚不清楚。线粒体DNA（mtDNA）单倍型群反映了 一个人的祖先的地理起源，并已与差异， 在高加索人（单倍型H）和非洲裔美国人之间观察到的心血管风险 （单倍群L）。一个人的mtDNA单倍型组是已知的差异影响氧化 磷酸化，从而线粒体效率，ATP周转，和生产 活性氧和其他代谢物。我们提出了一个高度创新的概念， 线粒体功能的差异影响促炎性先天免疫的激活 途径和随后的移植失败后HTx。nlrp 3炎性体的活化 在促炎细胞因子IL-1 β的加工和分泌中达到高潮。的nlrp 3 炎性小体在驱动与缺血/再灌注相关的病理中起关键作用 在心脏I/R的两种动物模型中， 急性心肌梗死患者的心脏功能。最大限度地减少I/R损伤也至关重要， 提高HTx后移植物存活率。线粒体作为一个平台，NLRP 3 炎性小体组装和线粒体损伤相关的分子模式（线粒体- DAMP）介导NLRP 3炎性体的引发和活化。使用 胚胎-核交换（MNX）小鼠模型，其中分离的胚胎原核 将一种小鼠品系的细胞植入另一种品系的去核胚胎中， 评估功能不同的线粒体对缺血性脑损伤的全身反应的重要性 损伤在人类中，我们将通过检查HTx结果的影响来询问种族差异。 线粒体DNA单倍型群对缺血性损伤的反应。我们的发现将使我们能够确定 预测移植物失败的新生物特征，允许早期干预以限制NLRP 3 炎性小体依赖性病理性炎症反应。

Project Summary Heart transplantation (HTx) is the only definitive treatment for end-stage heart failure if other medical or surgical treatments and interventions have failed. Despite advances in the management of HTx patients there remains a critical need to optimize long-term outcomes post- HTx. The cumulative risk of death in African-American HTx recipients is particularly high. While racial disparity in outcomes among African-American HTx recipients is well documented, the basis for this difference in is not understood. Mitochondrial DNA (mtDNA) haplogroups reflect an individual's ancestral geographic origin and have been correlated with the disparity in cardiovascular risk observed between Caucasians (haplogroup H) and African-Americans (haplogroup L). An individual's mtDNA haplogroup is known to differentially impact oxidative phosphorylation and consequently mitochondrial efficiency, ATP turnover, and the production of reactive oxygen species and other metabolites. We propose a highly innovate concept that racial differences in mitochondrial function influence the activation of proinflammatory innate immune pathways and subsequent graft failure after HTx. Activation of the NLRP3 inflammasome culminates in the processing and secretion of the proinflammatory cytokine IL-1beta. The NLRP3 inflammasome plays a critical role in driving the pathology associated with ischemia/reperfusion (I/R) injury and targeting this pathway has proven beneficial in both animal models of cardiac I/R injury and in patients with acute myocardial infarction. Minimizing I/R injury is also critical for improving graft survival following HTx. Mitochondria serve as a platform upon which the NLRP3 inflammasome assembles and mitochondrial damage-associated molecular patterns (mito- DAMPs) mediate the priming and activation of the NLRP3 inflammasome. Using the mitochondrial-nuclear exchange (MNX) mouse models, in which isolated embryonic pro-nuclei from one mouse strain are implanted into an enucleated embryo of a different strain, we will assess the importance of functionally distinct mitochondria on the systemic response to ischemic injury. In humans we will interrogate racial disparity in HTx outcomes by examining the impact of mtDNA haplogroups on the response to ischemic injury. Our findings will allow us to identify novel bio-signatures predictive of graft failure allowing for early intervention to limit the NLRP3 inflammasome-dependent pathologic inflammatory response.