Enhancing mtDNA Repair During Stroke Reperfusion to Reduce Brain Damage

增强中风再灌注期间 mtDNA 修复以减少脑损伤

基本信息

批准号：
8781394
负责人：
Glenn Wilson
金额：
$ 22.5万
依托单位：
EXSCIEN CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8781394
关键词：
8-Oxoguanine DNA Glycosylase Acute Alteplase Antioxidants Attenuated Base Excision Repairs Brain Brain Infarction Brain Injuries Brain Ischemia Businesses Cell Death Cell Fate Control Cell Survival Cells Cerebral Ischemia Cerebrovascular Disorders Chimeric Proteins Clinical Clinical Research Clinical Trials Coagulation Process Cultured Cells Cytolysis DNA Damage DNA Repair DNA Repair Enzymes DNA glycosylase DNA repair protein Disease Drug effect disorder Effectiveness Emergency Situation Enzymes Etiology Excision Fetal Lung Genetic Genome Hydrogen Peroxide Hyperoxia In Vitro Injury Intervention Ischemia Laboratory Study Legal patent Lung Mechanics Mediating Middle Cerebral Artery Occlusion Mitochondria Mitochondrial DNA Modeling Molecular Molecular Target Mus Nature Nervous system structure New Agents Nuclear Organ Organ Transplantation Outcome Oxidants Perfusion Pharmaceutical Preparations Phase Play Population Purines Pyrimidine Reactive Oxygen Species Recording of previous events Recovery Reperfusion Injury Reperfusion Therapy Research Personnel Rodent Model Role Sentinel Signal Transduction Stroke Testing Therapeutic Therapeutic Uses Tissues Uncertainty Universities Vascular Endothelial Cell Ventilator Work acute stroke base cell type clinically relevant cytotoxicity design expectation functional outcomes improved in vivo injured innovation lung injury mortality novel oxidant stress oxidative DNA damage oxidative damage prevent public health relevance purine repaired response stroke therapy

项目摘要

DESCRIPTION (provided by applicant): Attempts to develop drug treatments for acute stroke have not fulfilled expectations. Perhaps best illustrating this unsatisfactory situation is the hisory of therapeutic strategies directed at the inhibition of reactive oxygen species (ROS). While decades of laboratory and clinical studies make it clear that ROS are pathogenically important across the entire spectrum of cerebrovascular disease, as well as many other disorders, the beneficial effects of anti-oxidants in clinical trials for stroke have been unimpressive. These negative outcomes may be attributed in part to the heterogeneous nature of cerebral ischemia, which tends to obfuscate the design and interpretation of clinical trials. There also remains considerable scientific uncertainty about the molecular targets of anti-oxidant drug action. For example, non-selective antioxidants may disrupt signaling required for cell survival and recovery. The strategies currently available may not target the key sentinel molecule(s) that integrate the cellular effects of ROS and ROS signaling. Mitochondrial DNA (mtDNA) is far more sensitive to oxidative damage than the nuclear genome. Further, multiple lines of evidence support the idea that mtDNA serves as a molecular sentinel controlling cell fate in response to oxidant stress. There is also a conspicuous association between mtDNA damage and oxidant- induced cell death: the propensity for cytotoxicity is inversely related to the efficiency of mtDNA repair. We have shown this relationship in ischemic brain. Moreover, it has been found that in the nervous system, 8- oxoguanine DNA glycosylase (Ogg1), the first enzyme in base excision repair, is neuroprotective in the setting of oxidative DNA damage in vitro and in modeled stroke in vivo. Based on these provocative findings, the small business concern, Exscien, and its university partners devised and patented novel fusion protein constructs targeting DNA repair glycosylases to mitochondria and demonstrated in clinically-relevant rodent models that the new agents exert no off-target effects and suppress injury in several models of organ transplantation. We now propose to verify the efficacy of mitochondria-targeted DNA repair "drugs" in a different type of ischemia- reperfusion injury, namely stroke. The intent of this Phase I proposal is to establish proof-of-concept that pharmacologic enhancement of mtDNA repair attenuates the degree of brain infarction following reperfusion. This proposed application is innovative because it will herald first-in-class, platform molecules directed against a novel target in stroke, mtDNA, and many other disorders where oxidant stress plays a pathogenic role.

描述（由申请人提供）：开发治疗急性中风的药物的尝试尚未达到预期。也许最能说明这种令人不满意的情况的是针对活性氧（ROS）抑制的治疗策略的历史。尽管数十年的实验室和临床研究表明，ROS 在整个脑血管疾病以及许多其他疾病中具有重要的致病作用，但抗氧化剂在中风临床试验中的有益作用并不令人印象深刻。这些负面结果可能部分归因于脑缺血的异质性，这往往会混淆临床试验的设计和解释。关于抗氧化药物作用的分子靶标仍然存在相当大的科学不确定性。例如，非选择性抗氧化剂可能会破坏细胞存活和恢复所需的信号传导。目前可用的策略可能不针对整合 ROS 和 ROS 信号传导的细胞效应的关键前哨分子。线粒体 DNA (mtDNA) 对氧化损伤比核基因组更敏感。此外，多种证据支持线粒体 DNA 作为分子哨兵，控制细胞命运以应对氧化应激的观点。 mtDNA 损伤与氧化剂诱导的细胞死亡之间也存在明显的关联：细胞毒性的倾向与 mtDNA 的效率成反比维修。我们已经在缺血性脑中展示了这种关系。此外，研究发现，在神经系统中，8-氧代鸟嘌呤 DNA 糖基化酶 (Ogg1)（碱基切除修复中的第一个酶）在体外 DNA 氧化损伤和体内中风模型中具有神经保护作用。基于这些令人兴奋的发现，小型企业 Exscien 及其大学合作伙伴设计了针对线粒体的 DNA 修复糖基化酶的新型融合蛋白构建体并获得了专利，并在临床相关的啮齿动物模型中证明，新药物不会产生脱靶效应并抑制几种器官移植模型中的损伤。我们现在提议验证线粒体靶向 DNA 修复“药物”在不同类型的缺血再灌注损伤（即中风）中的功效。这一第一阶段提案的目的是建立概念验证，即药物增强 mtDNA 修复可减轻再灌注后脑梗死的程度。这项拟议的应用具有创新性，因为它将预示着针对中风、mtDNA、以及氧化应激发挥致病作用的许多其他疾病。