MtDNA repair: An isolated pharmacologic target in acute lung injury

MtDNA 修复：急性肺损伤的一个孤立的药理学靶点

基本信息

批准号：
10206228
负责人：
MARK N GILLESPIE
金额：
$ 41.84万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-16 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10206228
关键词：
Acute Acute Lung Injury Address Adult Respiratory Distress Syndrome Animal Model Automobile Driving Award Bacteria Bioenergetics Biological Biology Characteristics Clinical Critical Illness DNA Repair Enzymes DNA receptor Development Disease Disease Progression Distant Environment Event Evolution Fracture Functional disorder Generations Goals Human Hyperoxia Inflammatory Injury Laboratories Lead Link Lung Lung Transplantation Mitochondria Mitochondrial DNA Molecular Multiple Organ Failure New Agents Observational Study Organ Outcome Oxidants Oxidative Stress Pathogenesis Pathway interactions Patients Pattern Pattern Formation Pharmacology Plasma Pre-Clinical Model Process Production Reperfusion Injury Reporting Research Risk Sentinel Site Somatic Mutation Source Stress Testing Transfusion Transplantation Trauma patient Ventilator autoinflammatory base blood product clinical biomarkers cytokine cytotoxicity extracellular human subject innovation insight lung injury mitochondrial DNA mutation mitochondrial dysfunction mitochondrial genome operation outcome prediction oxidative damage prevent regenerative repaired response response to injury severe injury trafficking

项目摘要

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.

项目摘要/摘要线粒体（MT）功能障碍在急性呼吸窘迫综合征及其续集中常见器官系统故障，但与MT相关途径的潜力是作为药理目标 Ards和MOSF尚未实现。在来自该项目的发现中，两行证据可能具有范式转移的含义。首先，MTDNA修复的调节协调调节氧化mtDNA损伤和随之而来的细胞毒性。其次，氧化损坏的碎片化 mtDNA进入损伤相关的分子模式可能会通过激活A传播对遥远器官的损伤再生，喂养前途径，其中mtDNA潮湿损坏了线粒体基因组并促进更多mtDNA潮湿的形成。这些考虑为我们的长期提供了基础基于以下概念来制定药理策略来治疗ARD和MOSF的术语目标线粒体（MT）DNA充当疾病进展的分子前哨重症或受伤。由于我们发现输血产品的管理无意含有可变量的mtDNA潮湿会增加循环的mtDNA湿水平并提高风险严重受伤的患者的ARDS样输血相关的急性肺损伤，AIM 1将确定是否a 进料前途径有助于mtDNA潮湿在大规模转移的，批判性的受伤的人的受试者有Trali的风险。在这里，我们将测试外源量的假设在大规模输血期间给药的mtDNA决定了从内生，患者衍生的来源。第二个目的是基于以下事实：尽管氧化mtDNA 损坏导致潮湿释放，仅提供有关mtDNA机制的信息很少潮湿的碎片和序列特征如此形成。确实，这种缺陷存在解决与哪些碎片是生物学上有关的基本问题的严重障碍活跃以及它们如何被贩运在细胞内和细胞外环境中。因此，AIM 2将测试假设线粒体基因组氧化损伤部位促进其裂缝特定的mtDNA湿序序列，使MT基因组易于体细胞突变。集体，拟议的研究很重要，因为它将洞悉mtDNA潮湿的机制形成，mtDNA潮湿在对损伤的反应中的重要性以及它们作为药理的实用性目标。这是创新的，因为涉及mtDNA损坏的前馈途径的假设操作 - 诱导的潮湿形成是一种从根本上解释ARDS进行性发病机理的新概念和MOSF。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Elevated levels of plasma mitochondrial DNA DAMPs are linked to clinical outcome in severely injured human subjects.

DOI：
10.1097/sla.0b013e3182a4ea46
发表时间：
2013-10
期刊：
Annals of surgery
影响因子：
9
作者：
Simmons JD;Lee YL;Mulekar S;Kuck JL;Brevard SB;Gonzalez RP;Gillespie MN;Richards WO
通讯作者：
Richards WO

Pharmacologic Protection of Mitochondrial DNA Integrity May Afford a New Strategy for Suppressing Lung Ischemia-Reperfusion Injury.

DOI：
10.1513/annalsats.201706-438mg
发表时间：
2017-09
期刊：
Annals of the American Thoracic Society
影响因子：
8.3
作者：
Yong B. Tan;S. Mulekar;O. Gorodnya;M. Weyant;M. Zamora;J. Simmons;Tiago Machuka;M. Gillespie
通讯作者：
Yong B. Tan;S. Mulekar;O. Gorodnya;M. Weyant;M. Zamora;J. Simmons;Tiago Machuka;M. Gillespie

Potential contribution of mitochondrial DNA damage associated molecular patterns in transfusion products to the development of acute respiratory distress syndrome after multiple transfusions.

DOI：
10.1097/ta.0000000000001421
发表时间：
2017-06
期刊：
The journal of trauma and acute care surgery
影响因子：
0
作者：
Simmons JD;Lee YL;Pastukh VM;Capley G;Muscat CA;Muscat DC;Marshall ML;Brevard SB;Gillespie MN
通讯作者：
Gillespie MN

Mitochondrial DNA Damage Initiates Acute Lung Injury and Multi-Organ System Failure Evoked in Rats by Intra-Tracheal Pseudomonas Aeruginosa.

DOI：
10.1097/shk.0000000000000838
发表时间：
2017-07
期刊：
Shock (Augusta, Ga.)
影响因子：
0
作者：
Lee YL;Obiako B;Gorodnya OM;Ruchko MV;Kuck JL;Pastukh VM;Wilson GL;Simmons JD;Gillespie MN
通讯作者：
Gillespie MN

Mitochondrial Damage-associated Molecular Patterns as Potential Biomarkers in DCD Heart Transplantation: Lessons From Myocardial Infarction and Cardiac Arrest.