Mitochondrial Uncoupling as a Therapeutic Target in TBI

描述(申请人提供)：创伤性脑损伤(TBI)在美国是一个毁灭性的医疗问题，然而，目前还没有批准的药物治疗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。这项建议侧重于将轻度线粒体解偶联作为创伤性脑损伤后的一种新的治疗干预措施。其前提是颅脑损伤引起线粒体钙循环/超载增加，最终导致线粒体功能障碍。 线粒体解偶联剂是一种促进质子从线粒体内膜空间进入线粒体基质的化合物。解偶联也可以通过激活内源性线粒体解偶联蛋白(UCP)来介导，该蛋白可以被禁食调节。虽然线粒体长期的完全解偶联是有害的，但短暂的或“轻微的解偶联”可能会提供神经保护。颅脑损伤急性期轻度解偶联可能会减少线粒体钙摄取(循环)和ROS的产生。拟议的实验旨在检验这一新的假设，即轻微的线粒体解偶联在创伤性脑损伤后具有神经保护作用。具体地说，我们将确定1)线粒体解偶联器是否增加了脑损伤后的组织保存并改善了行为结果；2)线粒体解偶联器是否维持了脑损伤后线粒体的完整性和生物能量学；3)研究了创伤脑损伤后禁食提供神经保护的机制(S)。这些实验将确定损伤后使用解偶联剂的最佳剂量和时间，以提供最佳的神经保护，并减少大鼠轻度或严重脑外伤后的认知障碍。接下来，我们将检测轻度或重度脑外伤后大鼠的线粒体功能，以确定线粒体解偶联器是否维持线粒体的完整性。最后，使用简化论的方法，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给药，以确定涉及空腹介导的脑损伤后神经保护的特定机制。拟议中的实验可能会精确定位重要的线粒体事件，这些事件可能成为治疗脑外伤和其他急性神经元损伤的潜在新靶点。

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.