Targeting mitochondrial Complex I in neonatal hypoxia-ischemia

靶向线粒体复合物 I 在新生儿缺氧缺血中的作用

基本信息

批准号：
10442050
负责人：
BRIAN M POLSTER
金额：
$ 42.34万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-15 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10442050
关键词：
3-nitrotyrosine Acute Aftercare Animals Apoptosis Apoptotic Behavioral Assay Birth Brain Brain Hypoxia-Ischemia Cause of Death Cell Death Cells Cessation of life Chronic Clinical Cognitive Complex Data Development Diagnosis Dose Electron Transport Encephalopathies Energy Metabolism Epilepsy Event Exhibits Exposure to Failure Female Functional disorder Genetic Genetic Models Goals HMGB1 gene Hippocampus (Brain)Histopathology Hour Hyperoxia Hypoxic-Ischemic Brain Injury Immune Immunohistochemistry In Vitro Infant Care Inflammatory Inflammatory Response Injury Intervention Knock-in Mouse Label Lesion Measures Mediating Methods Microglia Mitochondria Modeling Morbidity - disease rate Motor Multiple Trauma Mus Myocardial Ischemia Neurologic Neurons Newborn Infant Outcome Outcome Measure Oxidative Stress Oxides Pathway interactions Pharmaceutical Preparations Phase Production Publishing Rattus Reactive Oxygen Species Recovery Reperfusion Therapy Residual state Respiration Rice Rodent Model Role Secondary to Series Signal Transduction Stains Succinates TLR4 gene Testing Therapeutic Tissues Work behavioral outcome blood-brain barrier permeabilization brain tissue clinical care cohort cytochrome c cytokine disability functional outcomes genetic signature improved in vivo inhibitor male mouse model natural hypothermia neonatal hypoxic-ischemic brain injury neurodevelopment neuroinflammation neuroprotection novel oxidation postnatal pre-clinical prevent response sex sexual dimorphism translational approach

项目摘要

Project Summary Neonatal hypoxic ischemic encephalopathy (HIE) is characterized by a protracted series of pathophysiological events that, without intervention, are devastating. HIE can result in neurodevelopmental delays, epilepsy, cognitive and motor issues, or death. The current standard of clinical care for infants born at term with severe hypoxia-ischemia (HI) is hypothermia. Therapeutic hypothermia reduces the likelihood of death and lessens deficits in some behavioral outcome measures. However, neuroprotection is far from complete. The major goal of this proposal is to use the well-established Rice-Vannucci HI rodent model to develop a translational strategy for improving neuroprotection by targeting mitochondrial Complex I. Although Complex I function is necessary for the recovery of brain energy metabolism after acute energy failure, reactive oxygen species (ROS) produced by Complex I during the recovery phase contribute to secondary injury. Apoptotic cell death and neuroinflammation also contribute to hypoxic-ischemic brain injury. It is unknown whether these mechanisms depend on Complex I alterations in vivo. Our published findings demonstrate that the preclinical drug mdivi-1 inhibits Complex I-dependent ROS production while only mildly and reversibly inhibiting mitochondrial respiration. Our new data suggest a direct interaction of mdivi-1 with a subunit of Complex I. We find that mdivi- 1 significantly reduces the occurrence of severe rat brain tissue loss measured 3 days after HI and decreases 3-nitrotyrosine labeling, a marker of oxidative stress, in the hippocampus,. Mechanistically, we find that mdivi-1 interacts with Complex I in microglia, the innate immune cells mediating the persistent neuroinflammatory response after neonatal HI. Mdivi-1 shows inhibition of microglial pro-inflammatory responses in vitro and in vivo. The central hypothesis of this study is that mdivi-1 will additively enhance hypothermic neuroprotection in neonatal hypoxic-ischemic brain injury models by reducing Complex I-dependent oxidative stress. We predict benefit in both male and female animals, though through potentially sexually dimorphic mechanisms. Males and females differ in dominant cell death pathways, and males exhibit greater vulnerability to chronic microglial activation after HI. A novel mouse model of partial Complex I deficiency showing normal neurodevelopment will be used to establish whether neuroprotection by mdivi-1 or hypothermia is occluded by a moderate reduction in the level of assembled Complex I. This genetic method will also reveal whether Complex I dysfunction contributes to HI-induced apoptosis or neuroinflammation in the immature brain of either sex. Positive outcomes will support the development of reversible Complex I inhibitors for clinical use, with the hope that this class of drugs may ultimately help millions by reducing the devastating consequences of neonatal hypoxic ischemic encephalopathy.

项目摘要新生儿缺氧缺血性脑病（HIE）的特征是一系列持久的一系列没有干预的病理生理事件是毁灭性的。 Hie可以导致神经发育延迟，癫痫，认知和运动问题或死亡。当前针对婴儿的临床护理标准患有严重缺氧 - 缺血（HI）的术语是体温过低。治疗性低温降低了死亡的可能性并减少某些行为结果指标的缺陷。但是，神经保护远非完整。这该提案的主要目标是使用良好的稻米vannucci hi啮齿动物模型来开发翻译通过靶向线粒体复合物来改善神经保护的策略I。尽管复合物I功能是急性能量失败后，活性氧（ROS）恢复大脑能量代谢所必需的必要恢复阶段由复合物I产生的造成了继发性损伤。凋亡细胞死亡和神经炎症也导致缺氧缺血性脑损伤。这些机制是否未知取决于复杂的I变化体内。我们发表的发现表明临床前药物MDIVI-1 抑制复合物I依赖性ROS的产生，而仅轻度和可逆地抑制线粒体呼吸。我们的新数据表明MDIVI-1与复杂的亚基的直接相互作用。我们发现Mdivi- 1显着降低了HI后3天测得的严重大鼠脑组织损失的发生，并减少 3-硝基酪氨酸标记是海马中的氧化应激标记。从机械上讲，我们发现MDIVI-1 与小胶质细胞中的复合物I相互作用，介导持续神经炎症的先天免疫细胞新生儿HI后的响应。 MDIVI-1显示了体外和体内小胶质细胞促炎反应的抑制作用。这项研究的中心假设是MDIVI-1将添加增强低温神经保护作用在新生儿缺氧 - 缺血性脑损伤模型中，通过减少复杂的I依赖性氧化应激。我们预测尽管有潜在的性二态机制，但男性和雌性动物都受益。男性和雌性在主要的细胞死亡途径上有所不同，男性对慢性小胶质细胞表现出更大的脆弱性 HI之后激活。局部复合物I缺乏症的新型小鼠模型，显示正常的神经发育用于确定MDIVI-1或低温神经保护是否因中等降低而阻碍组装复合物的水平I。这种遗传方法还将揭示复杂I功能障碍是否有助于在任何性别的未成熟大脑中，高诱导的凋亡或神经炎症。积极的结果将支持开发可逆复合物I抑制剂临床使用，希望这种类药物可以最终通过减少新生儿缺血性缺血性脑病的毁灭性后果来帮助数百万。