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: 7223190
• 负责人: Patrick G Sullivan
• 金额: $ 6.35万
• 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/7223190
• 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，目前还没有药物治疗被批准用于这种疾病的临床治疗。令人信服的实验数据表明，线粒体功能障碍是脑损伤神经病理后遗症的关键环节。这一建议的重点是轻度线粒体解偶联作为一种新的治疗干预创伤性脑损伤。前提是tbi诱导的线粒体Ca2+循环增加/过载最终导致线粒体功能障碍。