MtDNA repair: An isolated pharmacologic target in acute lung injury

项目总结/摘要 线粒体（mt）功能障碍在急性呼吸窘迫综合征及其后遗症中很常见， 器官系统衰竭，但潜在的mt相关途径作为药理学目标， ARDS和MOSF尚未实现。在这个项目的发现中，有两条线 这些证据可能会产生范式转变的影响。首先，调节mtDNA修复协调调节 线粒体DNA氧化损伤和伴随的细胞毒性。第二，氧化损伤的碎片 线粒体DNA进入损伤相关的分子模式可能通过激活一种 线粒体DNA DAMPs本身破坏线粒体基因组的再生前馈途径 并促进更多mtDNA DAMP的形成。这些考虑因素为我们长期以来的工作提供了基础- 长期目标是开发治疗ARDS和MOSF的药理学策略， 线粒体（mt）DNA作为控制疾病进展的分子哨兵， 严重的疾病或伤害。出于我们的发现，输注产品的管理无意中 含有不同量的mtDNA DAMP会增加循环中mtDNA DAMP的水平， 在严重损伤患者中，Aim 1将确定是否存在 前馈途径有助于线粒体DNA DAMP积累， 有TRALI风险的受伤人类受试者。在这里，我们将测试假设，即外源性的量 在大量输血期间给予的mtDNA决定了从血液中动员的mtDNA DAMP的量。 内源性、患者源性。第二个目的是基于这样一个事实，即虽然氧化mtDNA 损伤导致DAMP释放，关于mtDNA的机制只有很少的信息 因此形成的DAMP的片段和序列特征。事实上，这些缺陷 解决与哪些mtDNA片段在生物学上 以及它们如何在细胞内和细胞外环境中被贩运。因此，目标2将测试 假设线粒体基因组氧化损伤位点促进其断裂成 特定的mtDNA DAMP序列，使线粒体基因组易于发生体细胞突变。统称 这项研究具有重要意义，因为它将深入了解线粒体DNA DAMP的机制 形成，线粒体DNA DAMPs在损伤反应中的重要性，以及它们作为药理学 目标它的创新之处在于，假定的涉及线粒体DNA损伤的前馈通路的操作- 诱导DAMP形成是解释ARDS进展性发病机制的一个全新概念 和MOSF。

PROJECT SUMMARY/ABSTRACT Mitochondrial (mt) dysfunction is common in the Acute Respiratory Distress Syndrome and its sequel, Multiple Organ System Failure, but the potential for mt-associated pathways to serve as pharmacologic targets in ARDS and MOSF has yet to be realized. Among the discoveries originating from this project, two lines of evidence may have paradigm-shifting implications. First, modulation of mtDNA repair coordinately regulates oxidative mtDNA damage and attendant cytotoxicity. And second, fragmentation of oxidatively damaged mtDNA into Damage Associated Molecular Patterns may disseminate injury to distant organs by activating a regenerative, feed-forward pathway in which mtDNA DAMPs, themselves, damage the mitochondrial genome and promote more mtDNA DAMP formation. These considerations provide the underpinnings for our long- term goal to develop pharmacologic strategies to treat ARDS and MOSF based on the concept that mitochondrial (mt) DNA acts as a molecular sentinel governing disease progression in response to critical illness or injury. Motivated by our finding that administration of transfusion products inadvertently containing variable amounts of mtDNA DAMPs increases circulating mtDNA DAMP levels and elevates the risk of ARDS-like Transfusion Related Acute Lung Injury in severely injured patients, Aim 1 will determine if a feed-forward pathway contributes to mtDNA DAMP accumulation in massively-transfused, critically injured human subjects at risk for TRALI. Here, we will test the hypothesis that the amount of exogenous mtDNA administered during massive transfusion dictates the amount of mtDNA DAMPs mobilized from endogenous, patient-derived sources. The second Aim is predicated on the fact that although oxidative mtDNA damage leads to DAMP release, only scant information is available concerning mechanisms of mtDNA fragmentation and sequence characteristics of the DAMPs so formed. Indeed, such deficiencies present serious obstacles to addressing fundamental questions pertaining to which mtDNA fragments are biologically active and how they are trafficked in the intra- and extracellular environments. Accordingly, Aim 2 will test the hypothesis that sites of oxidative damage to the mitochondrial genome promote its fracture into specific mtDNA DAMP sequences and predispose the mt-genome to somatic mutation. Collectively, the proposed research is significant because it will provide insight into the mechanisms of mtDNA DAMP formation, the importance of mtDNA DAMPs in the response to injury, and their utility as a pharmacologic target. It is innovative because the postulated operation of feedforward pathway involving mtDNA damage- induced DAMP formation is a fundamentally new concept to explain the progressive pathogenesis of ARDS and MOSF.