"Role of CXCR2 in beta-amyloid Induced Neurodegeneration"

“CXCR2 在 β-淀粉样蛋白诱导的神经变性中的作用”

• 批准号: 7125324
• 负责人: GUO-HUANG FAN
• 金额: $ 31.41万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-10-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7125324
• 关键词: Alzheimer' s disease; amyloid proteins; chemokine; chemokine receptor; human; neural degeneration; neuroprotectants; peptides; receptor; role

Chemokines are up-regulated in the brain of Alzheimer's disease patients and are produced after amyloid-beta stimulation of glial cells.Based on these initial findings, we propose the following hypothesis: 1) some (if not all) chemokines produced by the reactive glial cells protect neurons against the toxicity of amyloid-b peptide through activation of the cognate chemokine receptors. 2) Specific signaling pathways initiated by the chemokine receptors are involved in the chemokine receptor-mediated neuroprotection. 3) Chemokine receptors in the inflamed CNS become constitutively desensitized due to the over-stimulation of the receptors by the excessive chemokines and excitatory amino acids produced by the activated astrocytes and microglial cells, thus resulting in attenuation of the chemokine receptor-mediated neuroprotection in clinical settings, such as those occuring in Alzheimer's disease. I propose the following specific aims to test these hypotheses. Aim 1. To determine whether CXCR2 is involved in the protection against amyloid-b peptide-induced neuronal death using CXCR2 knock-out mice and a selective CXCR2 antagonist in transgenic mice overexpressing human mutant human amyloid precursor protein as experimental tools. Aim 2. To determine the signaling pathways of CXCR2 involved in the receptor-mediated neuroprotection against amyloid-b peptide -induced neuronal damage. . To examine the contribution of glutamate- and chemokine-induced receptor desensitization and impairment of receptor resensitization to the failure of CXCR2 overexpression in AD to protect against neurodegeneration: Several important fundamental understandings will result from our studies, all of which have signficance for the understanding of the pathogenesis of neurodegenerative disease and its therapeutic interruption or prevention. First, we will clarify the role of the CXCR2 receptor in neuroprotection from pathways activated by b-Amyloid protein, in vitro and in vivo, utilizing complementary morphological, functional and behavioral assessments. Second, we will test the hypothesis that chemokinemediated signaling relevant for neuroprotection is counteracted by NMDA via mechanisms related to interruption of CXCR2 recycling and regeneration of receptor sensitivity to endogenous chemokines produced in excess in pathological settings, providing evidence for useful strategies for therapeutic intervention in AD and other neurodegenerative diseases.

阿尔茨海默病患者大脑中的趋化因子上调，并在β-淀粉样蛋白之后产生 刺激神经胶质细胞。基于这些初步发现，我们提出以下假设：1）一些（如果 并非全部）反应性神经胶质细胞产生的趋化因子可保护神经元免受淀粉样蛋白-b 的毒性 通过激活同源趋化因子受体来产生肽。 2) 启动的特定信号通路 趋化因子受体参与趋化因子受体介导的神经保护作用。 3) 趋化因子 发炎的中枢神经系统中的受体由于过度刺激而变得本质性脱敏。 由激活的星形胶质细胞产生的过量趋化因子和兴奋性氨基酸受体 小胶质细胞，从而导致临床上趋化因子受体介导的神经保护作用减弱 环境，例如阿尔茨海默病中发生的情况。我提出以下具体目标来测试这些 假设。目的 1. 确定 CXCR2 是否参与针对淀粉样蛋白-b 肽诱导的保护 使用 CXCR2 敲除小鼠和转基因小鼠中的选择性 CXCR2 拮抗剂导致神经元死亡 过度表达人类突变型人类淀粉样前体蛋白作为实验工具。目标 2. 确定 CXCR2信号通路参与受体介导的针对淀粉样蛋白-b的神经保护 肽诱导的神经元损伤。 。检查谷氨酸和趋化因子诱导的贡献 CXCR2 过表达失败导致受体脱敏和受体再敏受损 AD 预防神经退行性疾病：我们将得出几个重要的基本理解 这些研究对于理解神经退行性疾病的发病机制具有重要意义 疾病及其治疗中断或预防。首先，我们要阐明CXCR2受体在 利用互补的方法在体外和体内对 b-淀粉样蛋白激活的途径进行神经保护 形态、功能和行为评估。其次，我们将检验趋化因子介导的假设 NMDA 通过以下相关机制抵消与神经保护相关的信号传导： CXCR2 循环的中断和受体对内源趋化因子敏感性的再生 在病理环境中产生过量，为有效的治疗策略提供了证据 干预 AD 和其他神经退行性疾病。