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

NLRP3炎症小体在心肌缺血再灌注损伤和心脏移植中的线粒体调控

• 批准号: 10306406
• 负责人: Fayyaz S. Sutterwala
• 金额: $ 20.88万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-11-20 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10306406
• 关键词: Acute myocardial infarction; African; African American; African American population; Animal Model; Automobile Driving; CASP1 gene; Caspase; Caucasians; Cell Nucleus; Cells; Clinical Trials; Early Intervention; Embryo; Extracellular Space; Geography; Graft Rejection; Graft Survival; Haplogroup; Heart Transplantation; Heart failure; Human; Immune signaling; Implant; Individual; Inflammasome; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Innate Immune Response; Interleukin-1; Interleukin-1 Receptors; Interleukins; Intervention; Ischemia; Mediating; Medical; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Mouse Strains; Myocardial Ischemia; Natural Immunity; Nuclear; Operative Surgical Procedures; Outcome; Oxidative Phosphorylation; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Pattern Recognition; Pattern recognition receptor; Play; Pluripotent Stem Cells; Process; Production; Reactive Oxygen Species; Regulation; Reperfusion Injury; Reperfusion Therapy; Role; Signal Transduction; Tissues; Transplant Recipients; cardioprotection; cardiovascular risk factor; cytokine; graft failure; improved; induced pluripotent stem cell; innate immune pathways; innovation; ischemic injury; mortality risk; mouse model; myocardial injury; novel; patient population; predictive signature; racial difference; racial disparity; response

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.

项目摘要 如果其他 医疗或手术治疗和干预措施失败了。尽管进步 HTX患者的管理仍然是优化长期结局的迫切需要 htx。非裔美国人HTX接受者死亡的累积风险特别高。尽管 非洲裔美国人HTX接收者的种族差异已得到充分记录， 这种差异的基础尚不理解。线粒体DNA（mtDNA）单倍体反射 一个人的祖先地理起源，与差异相关 高加索人（单倍群H）和非裔美国人之间观察到的心血管风险 （单倍群）。已知个体的mtDNA单倍群可以差异影响氧化。 磷酸化，因此是线粒体效率，ATP离职和产生 活性氧和其他代谢产物。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的先天免疫的激活 HTX后的途径和随后的移植失败。 NLRP3炎性体的激活 最终在促炎性细胞因子IL-1Beta的加工和分泌方面达到高潮。 NLRP3 炎性体在驱动与缺血/再灌注相关的病理学方面起着关键作用 （I/R）受伤和针对此途径在两种心脏I/R动物模型中都有益 受伤和急性心肌梗塞的患者。最小化I/R伤害对于 HTX后改善移植物存活率。线粒体充当NLRP3的平台 炎性体组装和线粒体损伤相关的分子模式（线粒体 - 潮湿）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，其中孤立的胚胎蛋白核心 从一个小鼠菌株中植入不同菌株的浓缩胚胎，我们将 评估功能上不同线粒体对系统性反应的重要性 受伤。在人类中，我们将通过检查影响来审问HTX结果中的种族差异 mtDNA单倍群对缺血性损伤的反应。我们的发现将使我们能够确定 新型的生物签名可​​预测移植失败，允许早期干预限制NLRP3 炎性依赖性病理炎症反应。

项目成果

Inflammasome-Independent Roles of NLR and ALR Family Members.

NLR 和 ALR 家族成员的独立于炎症体的作用。

• DOI: 10.1007/978-1-0716-3350-2_2
• 发表时间: 2023
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Gupta,Suman;Cassel,SuzanneL;Sutterwala,FayyazS
• 通讯作者: Sutterwala,FayyazS