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.

项目概要新生儿缺氧缺血性脑病（HIE）的特点是一系列长期的如果不进行干预，就会产生毁灭性的病理生理事件。 HIE 可导致神经发育障碍延误、癫痫、认知和运动问题或死亡。目前出生婴儿的临床护理标准严重缺氧缺血（HI）的术语是体温过低。治疗性低温可降低死亡的可能性并减少一些行为结果指标的缺陷。然而，神经保护还远未完成。这该提案的主要目标是使用成熟的 Rice-Vannucci HI 啮齿动物模型来开发一种转化模型通过靶向线粒体复合物 I 来改善神经保护的策略。虽然复合物 I 的功能是急性能量衰竭后恢复脑能量代谢所必需的活性氧（ROS）复合物 I 在恢复阶段产生的物质会导致继发性损伤。细胞凋亡和神经炎症也会导致缺氧缺血性脑损伤。尚不清楚这些机制是否取决于体内复合物 I 的改变。我们发表的研究结果表明，临床前药物 mdivi-1 抑制复合物 I 依赖性 ROS 产生，同时仅轻度且可逆地抑制线粒体呼吸。我们的新数据表明 mdivi-1 与复合物 I 的亚基直接相互作用。我们发现 mdivi- 1 显着减少了 HI 后 3 天测量的严重大鼠脑组织丢失的发生率，并减少了 3-硝基酪氨酸标记，海马氧化应激的标志物。从机制上讲，我们发现 mdivi-1 与小胶质细胞中的复合物 I 相互作用，小胶质细胞是介导持续性神经炎症的先天免疫细胞新生儿 HI 后的反应。 Mdivi-1 在体外和体内均显示出对小胶质细胞促炎症反应的抑制作用。这项研究的中心假设是 mdivi-1 将额外增强低温神经保护作用通过减少复合物 I 依赖性氧化应激，在新生儿缺氧缺血性脑损伤模型中发挥作用。我们预测尽管通过潜在的性二态机制，雄性和雌性动物都受益。男性和女性的主要细胞死亡途径不同，而男性更容易受到慢性小胶质细胞的影响 HI 后激活。一种新型的复合物 I 部分缺乏的小鼠模型显示出正常的神经发育用于确定 mdivi-1 或低温的神经保护是否会因适度减少而被阻断组装的复合物 I 的水平。这种遗传方法还将揭示复合物 I 功能障碍是否会导致 HI 诱导的任何性别未成熟大脑的细胞凋亡或神经炎症。积极成果将支持开发可逆的复合物I抑制剂用于临床，希望这类药物可以通过减少新生儿缺氧缺血性脑病的破坏性后果，最终帮助数百万人。