Investigating the Role of Pioglitazone, mitoNEET and Mitochondria following TBI

研究 TBI 后吡格列酮、mitoNEET 和线粒体的作用

• 批准号: 8784017
• 负责人: HEATHER YONUTAS
• 金额: $ 3.3万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8784017
• 关键词: Agonist; American; Behavior; Binding; Bioenergetics; Brain Injuries; Cell Death; Clinical; Cognition; Cognitive; Data; Development; Diffusion Magnetic Resonance Imaging; Dose; FDA approved; Functional disorder; Glutamates; Goals; Healthcare; Hippocampus (Brain); Homeostasis; Hour; Ideal 1; Injury; Intervention; Investigation; Knockout Mice; Laboratories; Ligands; Literature; Magnetic Resonance; Maintenance; Measures; Mediating; Methods; Mitochondria; Mitochondrial Membrane Protein; Motor; Mus; Neurologic; Neurons; Outcome; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Pharmacological Treatment; Pioglitazone; Recovery of Function; Research; Respiration; Role; Science; Severities; Site; Synapses; Techniques; Testing; Therapeutic Agents; Therapeutic Effect; Tissues; Training; Traumatic Brain Injury; United States; Weight; Wild Type Mouse; cognitive change; cognitive recovery; controlled cortical impact; dosage; drug discovery; excitotoxicity; improved; in vivo; injured; mitochondrial dysfunction; morris water maze; neuron loss; neuropathology; neuroprotection; novel; protective effect; public health relevance; regenerative; response; therapeutic target

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) causes severe complications to the estimated 1.7 million Americans who are injured annually. This has precipitated a major focus on the discovery and development of neuroprotective and pro-regenerative therapeutic agents. One potential neuroprotective target, which has been well supported in the literature, is mitochondrial dysfunction resulting from TBI induced excitotoxicity This excitotoxicity is caused by excessive synaptic glutamate and the consequent over-excitation of neurons at the site of injury leading to large increases in mitochondrial Ca2+ cycling/Ca2+ overload. Ca2+ overload precedes a notable decrease in mitochondrial respiration, which has been documented in the first 3 to 48 hours post-injury. This decreased mitochondrial respiration, which is an indication of decreased mitochondrial bioenergetics (ability to generate ATP), leads to the initiation of cell death pathways. As the injured neurons die, the extent of tissue damage increases and functional (motor and cognitive) abilities decrease. We believe mitochondrial dysfunction to be a pivotal component to the neuropathological sequelae of brain injury and an important therapeutic target for drug discovery research in TBI. An overall goal of our laboratory is to determine whether amelioration of mitochondrial dysfunction will decrease the neuronal cell death associated with TBI. Findings from our lab and others show that pioglitazone, a known PPAR-? agonist, is neuroprotective and increases functional recovery following TBI. In support of this and the goals of our lab, pioglitazone not only reduces mitochondrial dysfunction following TBI, but also binds to mitoNEET, a novel mitochondrial membrane protein. However, the contribution of mitoNEET to pioglitazone- mediated neuroprotection is unknown. Preliminary results indicate that pioglitazone-mediated neuroprotection is absent in mitoNEET knockout mice and a specific mitoNEET ligand (NL-1) is neuroprotective following TBI. Taken together, these data suggest that mitoNEET is an essential component of pioglitazone mediated neuroprotection. Therefore, in order to understand the mechanisms of pioglitazone, I will test the hypothesis that pioglitazone's ability to improve mitochondrial bioenergetics, thereby decreasing tissue loss and improving functional recovery following TBI, hinges on binding mitoNEET. I further hypothesize that the protective effects of pioglitazone can be reproduced by NL-1, an exogenous mitoNEET ligand.

描述（由申请人提供）：创伤性脑损伤（TBI）导致估计每年受伤的170万美国人的严重并发症。这主要关注神经保护和促进性治疗剂的发现和发展。 One potential neuroprotective target, which has been well supported in the literature, is mitochondrial dysfunction resulting from TBI induced excitotoxicity This excitotoxicity is caused by excessive synaptic glutamate and the consequent over-excitation of neurons at the site of injury leading to large increases in mitochondrial Ca2+ cycling/Ca2+ overload. CA2+超负荷在线粒体呼吸的显着降低之前，这已经在伤害后的前3至48小时记录。线粒体呼吸减少，这表明线粒体生物能降低（产生ATP的能力），导致了细胞死亡途径的启动。随着受伤的神经元死亡，组织损伤的程度增加，功能（运动和认知）能力降低。我们认为线粒体功能障碍是脑损伤神经病理后遗症的关键成分，也是TBI药物发现研究的重要治疗靶点。我们实验室的总体目标是确定线粒体功能障碍的改善是否会减少与TBI相关的神经元细胞死亡。我们实验室和其他人的发现表明，吡格列酮是已知的PPAR-？激动剂是神经保护作用，并增加了TBI后的功能恢复。为了支持这一目标和实验室的目标，吡格列酮不仅降低了TBI后线粒体功能障碍，而且还与Mitoneet结合，Mitoneet是一种新型的线粒体膜蛋白。然而，米特内特对吡格列酮介导的神经保护的贡献尚不清楚。初步结果表明，在Mitoneet敲除小鼠中，吡格列酮介导的神经保护不存在，而特定的Mitoneet配体（NL-1）是TBI后神经保护性的。综上所述，这些数据表明Mitoneet是吡格列酮介导的神经保护作用的重要组成部分。因此，为了了解吡格列酮的机制，我将检验以下假设：吡格列酮可以改善线粒体生物能的能力，从而减少组织损失并改善TBI后的功能恢复，呈现在结合Mitoneet上。我进一步假设，吡格列酮的保护作用可以由外源线虫配体NL-1再现。