Role of NADPH Oxidase in TBI Pathology

NADPH 氧化酶在 TBI 病理学中的作用

• 批准号: 8763868
• 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/8763868
• 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; targeted treatment; 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标志性损伤，因此代表了从这些战争中返回的退伍军人的主要健康问题。迫切需要新的治疗方法来预防TBI引起的脑损伤，改善功能结果，并降低与TBI相关的痴呆风险。在本申请中，我们提出NADPH氧化酶，一种产生高活性和破坏性的自由基超氧化物的膜酶，在脑外伤后皮质和海马损伤、认知能力下降、痴呆风险增加和情感功能障碍中起关键作用。我们进一步提出，针对抑制NADPH氧化酶激活或其关键上游和下游介质的疗法将在退伍军人TBI的治疗中具有显著疗效。具体目标1将进行临床前研究，以确定NADPH氧化酶抑制剂在TBI后发挥神经保护作用和改善功能结果的功效。该目标将确定用于临床的治疗窗口、最佳剂量和最佳NADPH氧化酶抑制剂。特异性目的2将确定上游因子PTEN和Rac 1在NOX 2 NADPH氧化酶活化和TBI病理中的作用，并探索它们作为TBI潜在的新型上游治疗靶点的效用。目前还没有关于TBI中Rac 1和PTEN的研究，因此这些研究非常新颖。Rac 1激活是NOX 2激活所必需的，因此靶向其进行抑制可能会导致强大的神经保护和改善TBI的功能结果。PTEN是Akt的关键负调节因子，Akt是一种众所周知的促存活因子。因此，靶向PTEN进行抑制将为TBI后增强的促存活信号传导提供新的和潜在的稳健机制。具体目标3将确立JNK-Jun信号传导在TBI后介导NADPH氧化酶诱导的病理学中的作用。我们提出，NADPH氧化酶诱导的AD相关蛋白的上调和由此产生的神经变性是通过下游JNK-Jun信号转导介导的转录和翻译后机制实现的。NOX 2敲除小鼠和NADPH氧化酶抑制剂研究将用于确定TBI后NOX 2对JNK/Jun信号通路诱导的调节作用。JNK抑制也将用于确定JNK/Jun信号传导在TBI后AD相关蛋白诱导、神经变性和功能结果中的作用。总的来说，这些研究将加深我们对TBI病理机制的理解，并有可能产生重要的TBI新疗法。