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

项目摘要 心脏移植(HTX)是治疗终末期心力衰竭的唯一权威疗法，如果有其他 内科或外科治疗和干预都失败了。尽管在这方面取得了进展 HTX患者的管理仍然迫切需要优化术后的长期结果 HTX。非裔美国人HTX接受者的累积死亡风险特别高。而当 非裔美国人HTX接受者之间的种族差异是有充分证据的， 这种差异的基础还不清楚。线粒体DNA(MtDNA)单倍群反映 一个人的祖籍地理来源，并与 观察到高加索人(单倍群H)和非裔美国人之间的心血管风险 (单倍群L)。已知个体的mtDNA单倍群对氧化的影响是不同的 磷酸化，进而线粒体效率，ATP周转率，以及产生 活性氧类和其他代谢物。我们提出了一个高度创新的概念，种族 线粒体功能的差异影响促炎先天免疫的激活 HTX后的途径和随后的移植物失败。NLRP3炎症体的激活 在促炎细胞因子IL-1β的加工和分泌过程中达到顶峰。NLRP3 炎性小体在推动与缺血/再灌注相关的病理过程中起着关键作用 (I/R)损伤和靶向该通路已被证明在两种心脏I/R动物模型中都是有益的 在损伤和急性心肌梗死患者中。将I/R损伤降至最低也至关重要 提高HTX术后移植物存活率。线粒体作为NLRP3的平台 炎性小体组装和线粒体损伤相关分子模式(mito- DAMPS)介导NLRP3炎症体的启动和激活。使用 线粒体-核交换(MNX)小鼠模型，在该模型中分离胚胎原核 被植入另一种品系的去核胚胎，我们将 评估功能不同的线粒体在全身缺血反应中的重要性 受伤。在人类身上，我们将通过检查HTX结果的影响来询问种族差异 线粒体DNA单倍群对缺血损伤的反应。我们的发现将使我们能够确定 预测移植失败的新生物标志允许早期干预以限制NLRP3 依赖炎症体的病理性炎症反应。

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.