Role of NADPH Oxidase in TBI Pathology

NADPH 氧化酶在 TBI 病理学中的作用

• 批准号: 8541974
• 负责人: DARRELL W BRANN
• 金额: --
• 依托单位: CHARLIE NORWOOD VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8541974
• 关键词: Address; Afghanistan; Aftercare; Alzheimer' s Disease; Attenuated; Behavioral; Biphasic Pattern; Brain; Brain Injuries; Cause of Death; Clinic; Cognitive; Complex; Data; Dementia; Diagnosis; Dose; Emotional; Enzymes; Event; Free Radicals; Functional disorder; Generations; Genes; Health; Hippocampus (Brain); Impaired cognition; Injury; Investigation; Iraq; Knockout Mice; Laboratories; Lead; Lipids; Mediating; Mediator of activation protein; Membrane; Microglia; N-terminal; NADPH Oxidase; Nerve Degeneration; Oxidative Stress; PTEN gene; Pathology; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Play; Preclinical Testing; Production; Proteins; Reactive Oxygen Species; Research; Risk; Role; Signal Pathway; Signal Transduction; Soldier; Superoxides; Testing; Therapeutic; Translations; Traumatic Brain Injury; Treatment Efficacy; United States; United States Department of Veterans Affairs; Up-Regulation; Veterans; War; Work; antioxidant therapy; base; beta-site APP cleaving enzyme 1; brain cell; disability; functional outcomes; improved; inhibitor/antagonist; neuroprotection; novel; preclinical study; prevent; public health relevance; statistics; success; tau Proteins; therapeutic target

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a hallmark injury to soldiers on the battlefield in Iraq and Afghanistan and thus represents a major health issue for veterans returning from these wars. New therapies are urgently needed to prevent brain damage from TBI, improve functional outcomes, and reduce the enhanced risk of dementia associated with TBI. In this application, we propose that NADPH oxidase, a membrane enzyme that generates the highly reactive and damaging free radical superoxide, plays a critical role in cortical and hippocampal damage, cognitive decline, increased risk of dementia, and emotional dysfunction following TBI. We further propose that therapies targeted at inhibiting NADPH oxidase activation, or its key upstream and downstream, mediators will have significant efficacy in the treatment of TBI in veterans. Specific Aim 1 would perform preclinical studies to determine the efficacy of NADPH oxidase inhibitors in exerting neuroprotection and improving functional outcome after TBI. This aim would determine what are the therapeutic window, optimal dose, and optimal NADPH oxidase inhibitor for translation to the clinic. Specific Aim 2 would determine the role of the upstream factors, PTEN and Rac1 in NOX2 NADPH oxidase activation and TBI pathology, and explore their utility as potential novel upstream therapeutic targets in TBI. There are no studies on either Rac1 and PTEN in TBI, and thus the studies are highly novel. Rac1 activation is required for NOX2 activation, and thus targeting it for inhibition could lead to powerful neuroprotection and improved functional outcome in TBI. PTEN is a critical negative regulator of Akt, a well known pro-survival factor. Targeting PTEN for inhibition would thus offer a novel and potentially robust mechanism for enhanced pro-survival signaling following TBI. Specific Aim 3 would establish the role of JNK-Jun signaling in mediating NADPH oxidase-induced pathology following TBI. We propose that NADPH oxidase-induced up-regulation of AD-related proteins and resultant neurodegeneration is achieved via both transcriptional and post- translational mechanisms that are mediated by downstream JNK-Jun signaling. NOX2 knockout mice and NADPH oxidase inhibitor studies will be used to determine the regulatory role of NOX2 on JNK/Jun signaling pathway induction after TBI. JNK inhibition will also be used to determine the role of JNK/Jun signaling in AD-related protein induction, neurodegeneration and functional outcome following TBI. As a whole, the studies will enhance our understanding of the pathological mechanisms underlying TBI, and have the potential to yield important new therapies for TBI.

描述(由申请人提供)： 创伤性脑损伤(TBI)是伊拉克和阿富汗战场上士兵的一种标志性损伤，因此是从这些战争中归来的退伍军人的一个主要健康问题。迫切需要新的治疗方法来预防脑损伤，改善功能结果，并降低与脑损伤相关的痴呆症风险增加。在这一应用中，我们认为NADPH氧化酶，一种产生高活性和破坏性的自由基超氧化物的细胞膜酶，在脑创伤后皮质和海马区损伤、认知功能减退、痴呆风险增加和情感功能障碍中发挥关键作用。我们进一步提出，以抑制NADPH氧化酶激活或其关键的上游和下游介质为目标的疗法将在退伍军人脑外伤的治疗中具有显著的疗效。具体目标1将进行临床前研究，以确定NADPH氧化酶抑制剂在发挥神经保护作用和改善脑外伤后功能预后方面的效果。这一目标将决定什么是治疗窗口，最佳剂量，以及最佳NADPH氧化酶抑制剂，以转移到临床。特异性目标2将确定上游因子PTEN和rac1在NOX2 NADPH氧化酶激活和脑损伤病理中的作用，并探索它们作为潜在的脑损伤上游治疗靶点的应用。目前，在脑损伤中还没有关于rac1和PTEN的研究，因此这些研究具有很高的新颖性。NOX2的激活需要rac1的激活，因此针对它的抑制可能会导致强大的神经保护和改善脑损伤的功能结局。PTEN是Akt的关键负性调节因子，Akt是众所周知的促生存因子。因此，以PTEN为靶点进行抑制将为脑外伤后增强促生存信号提供一种新的、潜在的强大机制。特异目的3将确定JNK-JUN信号在介导NADPH氧化酶诱导的脑损伤后病理中的作用。我们认为，NADPH氧化酶诱导AD相关蛋白表达上调和导致的神经变性是通过转录和翻译后机制实现的，这些机制是由下游的JNK-Jun信号介导的。NOX2基因敲除小鼠和NADPH氧化酶抑制剂的研究将确定NOX2在脑创伤后JNK/JUN信号通路诱导中的调节作用。JNK抑制也将被用来确定JNK/Jun信号在脑创伤后AD相关蛋白诱导、神经退行性变和功能结果中的作用。总体而言，这些研究将加深我们对脑外伤潜在的病理机制的理解，并有可能为脑外伤提供重要的新疗法。