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）：每年估计有 170 万美国人受伤，创伤性脑损伤 (TBI) 会导致严重的并发症。这引发了对神经保护和促再生治疗剂的发现和开发的主要关注。一个潜在的神经保护目标是由 TBI 诱导的兴奋性毒性引起的线粒体功能障碍，这一点已得到文献的充分支持。这种兴奋性毒性是由过量的突触谷氨酸和随后损伤部位神经元的过度兴奋引起的，导致线粒体 Ca2+ 大量增加循环/Ca2+超载。 Ca2+ 超载先于线粒体呼吸显着下降，这在损伤后的前 3 至 48 小时内已有记录。线粒体呼吸的减少表明线粒体生物能（产生 ATP 的能力）下降，从而导致细胞死亡途径的启动。随着受伤神经元的死亡，组织损伤的程度会增加，功能（运动和认知）能力会下降。我们相信线粒体功能障碍是脑损伤神经病理学后遗症的关键组成部分，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。我们实验室和其他实验室的研究结果表明，吡格列酮（一种已知的 PPAR-？）激动剂，具有神经保护作用，可促进 TBI 后的功能恢复。为了支持这一点和我们实验室的目标，吡格列酮不仅可以减少 TBI 后的线粒体功能障碍，而且还可以与 mitoNEET（一种新型线粒体膜蛋白）结合。然而，mitoNEET 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，mitoNEET 敲除小鼠中不存在吡格列酮介导的神经保护作用，并且特定的 mitoNEET 配体 (NL-1) 在 TBI 后具有神经保护作用。综上所述，这些数据表明 mitoNEET 是吡格列酮介导的神经保护的重要组成部分。因此，为了了解吡格列酮的作用机制，我将检验以下假设：吡格列酮改善线粒体生物能，从而减少 TBI 后的组织损失并改善功能恢复的能力取决于与 mitoNEET 的结合。我进一步假设吡格列酮的保护作用可以通过 NL-1（一种外源 mitoNEET 配体）重现。