Mitochondrial Uncoupling as a Therapeutic Target in TBI

线粒体解偶联作为 TBI 的治疗靶点

基本信息

批准号：
7204185
负责人：
Patrick G Sullivan
金额：
$ 28.79万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
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/7204185
关键词：
2,4-Dinitrophenol 4 hydroxynonenal Abbreviations Acetoacetates Acids Acute Acute Brain Injuries Address Adenosine Triphosphate Adult Animals Attenuated Behavioral Bioenergetics Blood Glucose Brain Injuries Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone Cell Death Cell Survival Clinical Treatment Cognitive Condition Data Defect Dinitrophenols Disruption Dose Electron Transport End Point Event Excitatory Amino Acids Fasting Functional disorder G Cells Glutamates Healthcare Hippocampus (Brain)Homeostasis Hydroxybutyrates Hydroxyl Radical Hypoglycemia Injury Inner mitochondrial membrane Insulin Intervention Isoxazoles Ketone Bodies Ketones Ketoses Ketosis Knock-out Lead Light Link Measures Mediating Membrane Potentials Mitochondria Mitochondrial Matrix Modeling Morphology Movement Neuronal Injury Nonesterified Fatty Acids Outcome Pathway interactions Pharmacological Treatment Phase Process Production Proteins Proton Pump Protons Publishing Rain Rattus Reactive Oxygen Species Recovery of Function Role Synapses System Testing Therapeutic Therapeutic Intervention Time Tissues Transgenic Mice Traumatic Brain Injury UCP2 protein United States Up-Regulation Work alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid amino 3 hydroxy 5 methylisoxazole 4 propionate base behavior measurement beta-Hydroxybutyrate concept controlled cortical impact design excitotoxicity glucose metabolism improved injured innovation male mesoxalonitrile mitochondrial dysfunction mitochondrial membrane mitochondrial uncoupling protein morris water maze neuron loss neuropathology neuroprotection novel novel therapeutics phenylhydrazone protein expression research study therapeutic target uptake

2,4-Dinitrophenol 4 hydroxynonenal Abbreviations Acetoacetates Acids Acute Acute Brain Injuries Address Adenosine Triphosphate Adult Animals Attenuated Behavioral Bioenergetics Blood Glucose Brain Injuries Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone Cell Death Cell Survival Clinical Treatment Cognitive Condition Data Defect Dinitrophenols Disruption Dose Electron Transport End Point Event Excitatory Amino Acids Fasting Functional disorder G Cells Glutamates Healthcare Hippocampus (Brain)Homeostasis Hydroxybutyrates Hydroxyl Radical Hypoglycemia Injury Inner mitochondrial membrane Insulin Intervention Isoxazoles Ketone Bodies Ketones Ketoses Ketosis Knock-out Lead Light Link Measures Mediating Membrane Potentials Mitochondria Mitochondrial Matrix Modeling Morphology Movement Neuronal Injury Nonesterified Fatty Acids Outcome Pathway interactions Pharmacological Treatment Phase Process Production Proteins Proton Pump Protons Publishing Rain Rattus Reactive Oxygen Species Recovery of Function Role Synapses System Testing Therapeutic Therapeutic Intervention Time Tissues Transgenic Mice Traumatic Brain Injury UCP2 protein United States Up-Regulation Work alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid amino 3 hydroxy 5 methylisoxazole 4 propionate base behavior measurement beta-Hydroxybutyrate concept controlled cortical impact design excitotoxicity glucose metabolism improved injured innovation male mesoxalonitrile mitochondrial dysfunction mitochondrial membrane mitochondrial uncoupling protein morris water maze neuron loss neuropathology neuroprotection novel novel therapeutics phenylhydrazone protein expression research study therapeutic target uptake

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项目摘要

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）是美国毁灭性的医疗问题，但是，目前尚未批准用于此病的临床治疗的药理治疗。引人注目的实验数据表明，线粒体功能障碍是脑损伤神经病理学的关键联系。该提案的重点是轻度线粒体解偶联，作为脑损伤后一种新型的治疗干预措施。前提是TBI诱导的线粒体Ca2+循环/超载的增加最终导致线粒体功能障碍。线粒体解耦合器是促进质子从线粒体内膜空间移动到线粒体基质的化合物。也可以通过激活内源性线粒体解偶联蛋白（UCP）来介导，可以通过禁食调节。尽管长期，线粒体的完全解偶将有害，但短暂或“轻度解偶联”可能会赋予神经保护作用。在TBI急性期间的轻度解偶联有望减少线粒体Ca2+摄取（循环）和ROS产生。提出的实验旨在测试新的假设，即在创伤性脑损伤后，轻度线粒体解偶联是神经保护性的。具体而言，我们将确定1）如果线粒体未偶联剂会增加组织的较高组织并改善TBI后的行为结果2）如果TBI和3）在TBI和3）之后使用线粒体的完整性和生物能源维持线粒体完整性和生物能力，则检查在快速脑损伤后能够提供神经保护作用的机制。这些实验将确定最佳剂量和时间后的时间，以给管理解偶联物，以提供最佳的神经保护作用，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uno偶联剂是否保持线粒体完整性。最后，使用还原主义方法，我们将采用多种策略，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TBI后禁食介导的神经保护涉及的特定机制。提出的实验可能会指出重要的线粒体事件，这可能是治疗TBI以及其他急性神经元损伤的潜在新靶标。