Mitochondrial Uncoupling as a Therapeutic Target in TBI

线粒体解偶联作为 TBI 的治疗靶点

• 批准号: 7014574
• 负责人: Patrick G Sullivan
• 金额: $ 29.68万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7014574
• 关键词: 2,4 dinitrophenol; brain injury; calcium flux; cyanides; cytoprotection; electron transport; fasting; free radical oxygen; functional ability; genetically modified animals; hypoketonemic hypoglycemia; insulin; laboratory mouse; laboratory rat; membrane potentials; mitochondria; mitochondrial membrane; neuroprotectants; nutrition related tag; oxidative phosphorylation; trauma

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a devastating healthcare problem in the United States, however, there are currently no pharmacological treatments approved for the clinical treatment of this condition. Compelling experimental data demonstrates that mitochondrial dysfunction is a pivotal link in the neuropathological sequalae of brain injury. This proposal focuses on mild mitochondrial uncoupling as a novel therapeutic intervention following traumatic brain injury. The premise being that TBI-induced increases in mitochondrial Ca2+ cycling/overload ultimately lead to mitochondrial dysfunction. Mitochondrial uncouplers are compounds that facilitate the movement of protons from the mitochondrial inner-membrane space into the mitochondrial matrix. Uncoupling can also be mediated via the activation of endogenous mitochondrial uncoupling proteins (UCP) that can be modulated by fasting. While long-term, complete uncoupling of mitochondria would be detrimental, a transient or "mild uncoupling", could confer neuroprotection. Mild uncoupling during the acute phases of TBI would be expected to reduce mitochondrial Ca2+ uptake (cycling) and ROS production. The proposed experiments are designed to test the novel hypothesis that mild mitochondrial uncoupling is neuroprotective following traumatic brain injury. Specifically we will determine 1) if mitochondrial uncouplers increase tissue sparing and improve behavioral outcome following TBI 2) if mitochondrial uncouplers maintain mitochondrial integrity and bioenergetics following TBI and 3) examine the mechanism(s) underlying the neuroprotection afforded by fasting following traumatic brain injury. The experiments will determine the optimal dose and time post-injury to administer uncouplers to afford optimal neuroprotection and reduce cognitive defects following a mild or severe TBI in rats. Next we will examine mitochondrial function following mild or severe TBI in rats to determine if mitochondrial uncouplers maintain mitochondrial integrity. Finally, using a reductionist approach, we will employ several strategies including the use of UCP-2 transgenic mice, insulin-induced hypoglycemia and ketone administration to determine specific mechanisms involved in fasting-mediated neuroprotection following TBI. The proposed experiments may pinpoint important mitochondrial events that could be potential novel targets for the treatment of TBI and perhaps, other acute neuronal injuries.

描述（由申请人提供）：创伤性脑损伤（TBI）在美国是一个毁灭性的医疗保健问题，然而，目前还没有批准用于这种疾病的临床治疗的药物治疗。令人信服的实验数据表明，线粒体功能障碍是脑损伤的神经病理后遗症的关键环节。该建议侧重于轻度线粒体解偶联作为创伤性脑损伤后的一种新型治疗干预。前提是TBI诱导的线粒体Ca 2+循环/过载增加最终导致线粒体功能障碍。 线粒体解偶联剂是促进质子从线粒体内膜空间移动到线粒体基质中的化合物。解偶联也可以通过激活内源性线粒体解偶联蛋白（UCP）介导，其可以通过禁食调节。虽然线粒体的长期、完全解偶联将是有害的，但短暂或“轻度解偶联”可赋予神经保护作用。TBI急性期的轻度解偶联预期会减少线粒体Ca 2+摄取（循环）和ROS产生。所提出的实验旨在检验新的假设，即轻度线粒体解偶联在创伤性脑损伤后具有神经保护作用。具体而言，我们将确定1）线粒体解偶联剂是否增加组织保留并改善TBI后的行为结果，2）线粒体解偶联剂是否在TBI后保持线粒体完整性和生物能量学，以及3）检查创伤性脑损伤后禁食提供的神经保护的潜在机制。实验将确定损伤后给予解偶联剂的最佳剂量和时间，以提供最佳的神经保护并减少大鼠轻度或重度TBI后的认知缺陷。接下来，我们将检查大鼠轻度或重度TBI后的线粒体功能，以确定线粒体解偶联剂是否维持线粒体完整性。最后，使用还原论的方法，我们将采用几种策略，包括使用UCP-2转基因小鼠，胰岛素诱导的低血糖和酮的管理，以确定具体的机制，涉及禁食介导的神经保护TBI后。拟议的实验可以确定重要的线粒体事件，这些事件可能是治疗TBI和其他急性神经元损伤的潜在新靶点。