Estrogen, NADPH Oxidase, and Neurotrauma

雌激素、NADPH 氧化酶和神经创伤

• 批准号: 6890275
• 负责人: ANNADORA J BRUCE-KELLER
• 金额: $ 33.99万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6890275
• 关键词: NAD(P)H dehydrogenase; antiinflammatory agents; astrocytes; blood brain barrier; brain injury; cellular pathology; cytokine; enzyme activity; enzyme inhibitors; estrogen receptors; estrogens; genetically modified animals; glia; hormone regulation /control mechanism; hormone therapy; immunocytochemistry; laboratory mouse; neurons; neuroprotectants; neurotoxins; northern blottings; polymerase chain reaction; receptor expression; western blottings

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) afflicts almost 500,000 Americans a year, but unfortunately, existing treatments have only minimal ability to prevent secondary brain damage accompanying traumatic brain injury. Epidemiological data that suggests that women fare better then men following TBI, but the basis for this difference is not understood. It is likely that action of female sex hormones, particularly estrogen, may have significant effects on the progression of brain injury, and recent data from our laboratory suggests that estrogen has potent anti-inflammatory properties that could account for its ability to attenuate traumatic brain injury. In particular, data indicates that estrogen is able to decrease oxidative burst activity and subsequent redox-based inflammatory signaling in glial cells, thereby attenuating neurotoxic brain inflammation. Therefore, it is proposed that estrogen acts to preserve brain function following TBI by decreasing both blood-brain barrier (BBB) breech and neuronal injury, and that these distinct endpoints are mediated by a single mechanism: modulation of the glial oxidative burst. Specific Aim 1 will test the hypothesis that estrogen is able to significantly attenuate oxidative burst activity in astrocytes, microglial cells, and endothelial cells both in vitro and in vivo, and will determine the role of estrogen receptors in this process through use of estrogen receptor knockout mice. Specific Aim 2 will test the hypothesis that by directly interfering with oxidative burst activity, estrogen blocks the release of matrix metalloproteinases and thus preserves blood-brain barrier integrity in mice following traumatic brain injury. Specific Aim 3 will build upon these studies by testing the hypothesis that by decreasing oxidative burst activity and redox signaling, estrogen blocks the formation of neurotoxic inflammatory mediators (excitotoxins and cytokines), culminating in decreased injury and increased recovery following traumatic brain injury. Completion of these studies will result in a thorough understanding of the mechanisms of estrogen-mediated neuroprotection in TBI and could highlight a novel target for therapeutic intervention following brain trauma in both women and men.

描述（由申请人提供）：每年创伤性脑损伤（TBI）每年遭受近500,000名美国人的困扰，但不幸的是，现有治疗方法只有最低的能力可以预防伴随创伤性脑损伤的继发性脑损伤。 流行病学数据表明，女性的表现要比TBI的男性更好，但是这种差异的基础尚不清楚。女性性激素，尤其是雌激素的作用可能会对脑损伤的进展产生重大影响，而我们实验室的最新数据表明，雌激素具有有效的抗炎特性，可以说明其减轻创伤性脑损伤的能力。 特别是，数据表明雌激素能够降低氧化爆发活性和随后基于氧化还原细胞的炎症信号，从而减轻神经毒性脑炎症。因此，有人提出雌激素可以通过减少血脑屏障（BBB）臀位和神经元损伤来保持TBI后保持大脑功能，并且这些独特的终点是由单个机制介导的：胶质氧化爆发的调节。具体目标1将检验以下假设：雌激素能够在体外和体内显着减轻星形胶质细胞，小胶质细胞和内皮细胞的氧化爆发活性，并通过使用雌激素受体敲除小鼠来确定雌激素受体在此过程中的作用。特定目标2将检验以下假设：通过直接干扰氧化爆发活性，雌激素阻断了基质金属蛋白酶的释放，从而在创伤性脑损伤后保留小鼠中血脑屏障的完整性。 特定的目标3将通过测试以下假设，即通过降低氧化爆发活性和氧化还原信号传导，雌激素阻止了神经毒性炎性介质（兴奋毒素和细胞因子）的形成，最终导致降低的损伤和恢复性脑损伤后造成损伤。 这些研究的完成将导致对TBI中雌激素介导的神经保护的机制有透彻的理解，并可以突出男女脑创伤后的治疗干预措施的新颖靶标。