Role of NADPH Oxidase in TBI Pathology

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，因此对从这些战争中返回的退伍军人来说是一个重大的健康问题。迫切需要新的疗法来预防 TBI 造成的脑损伤、改善功能结果并降低与 TBI 相关的痴呆风险。在此应用中，我们提出 NADPH 氧化酶（一种膜酶，可产生高反应性和破坏性的自由基超氧化物）在皮质和海马损伤、认知能力下降、痴呆风险增加和 TBI 后情绪功能障碍中发挥关键作用。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对退伍军人 TBI 的治疗具有显着疗效。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 TBI 后功能结果方面的功效。这一目标将确定转化为临床的治疗窗、最佳剂量和最佳 NADPH 氧化酶抑制剂。具体目标 2 将确定上游因子 PTEN 和 Rac1 在 NOX2 NADPH 氧化酶激活和 TBI 病理学中的作用，并探索它们作为 TBI 潜在新型上游治疗靶点的实用性。目前还没有关于 TBI 中 Rac1 和 PTEN 的研究，因此这些研究非常新颖。 NOX2 激活需要 Rac1 激活，因此针对其进行抑制可能会产生强大的神经保护作用并改善 TBI 的功能结果。 PTEN 是 Akt 的关键负调节因子，Akt 是众所周知的促生存因子。因此，以 PTEN 为靶标进行抑制将为 TBI 后增强促生存信号传导提供一种新颖且潜在稳健的机制。具体目标 3 将确定 JNK-Jun 信号在介导 TBI 后 NADPH 氧化酶诱导的病理学中的作用。我们认为 NADPH 氧化酶诱导的 AD 相关蛋白上调以及由此产生的神经变性是通过下游 JNK-Jun 信号介导的转录和翻译后机制实现的。 NOX2 敲除小鼠和 NADPH 氧化酶抑制剂研究将用于确定 NOX2 对 TBI 后 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 AD 相关蛋白诱导、神经变性和 TBI 后功能结果中的作用。总的来说，这些研究将增强我们对 TBI 病理机制的理解，并有可能产生重要的 TBI 新疗法。

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.