SDF-1 and neurogenesis in HIV-1 associated dementia

摘要： 神经前体细胞(NPC)存在于整个生命过程中，并能补充神经元和胶质细胞(星形胶质细胞和 少突胶质细胞)通过神经发生，这个过程需要适当的迁移，增殖和 鼻咽癌的分化。神经退行性疾病中的神经发生似乎功能障碍，包括 HIV-1相关性痴呆(HAD)、阿尔茨海默氏症和帕金森氏症，其中死亡或受损的神经元 没有被替换。HAD是一种神经退行性疾病，HIV-1感染并激活了大脑单个核细胞 吞噬细胞(MP；血管周围巨噬细胞和小胶质细胞)介导改变大脑的炎症状态。 动态平衡。我们最近证实，HIV-1感染和激活的巨噬细胞抑制神经发生。 但会促进神经胶质的生成。我们认为这种神经胶质的发生是通过脑部炎症来实现的。 基质细胞衍生因子-1(SDF-1)的异常调节。SDF-1是趋化因子的内源性配体 受体CXCR4，在人鼻咽癌上高表达，并介导鼻咽癌的迁移。SDF-1不正确 CXCR4功能可能通过影响鼻咽癌的迁移而影响神经修复。发布SDF-1以响应 HIV-1感染的炎性细胞因子和IL等激活的MP介导的胶质细胞激活 一种β(IL-1)。HAD患者脑脊液中SDF-1水平升高。活化矩阵 金属蛋白酶-2(MMP2)是由HIV-1感染和激活的MP产生的，并裂解SDF-1，导致 神经毒性碎片。这项建议将研究HIV-1感染和激活的巨噬细胞在 脑部炎症及其对神经发生的影响。我们假设HIV-1感染并免疫- 活化的MP抑制神经元分化，促进神经胶质形成。具体地说，我们建议这样做 神经发生的转变依赖于激活的星形胶质细胞产生的SDF-1。这种神经胶质形成 可能是HIV-1感染者释放的因子修饰/降解SDF-1的结果 MP导致正常SDF-1/CXCR4介导的鼻咽癌迁移、存活、增殖和 分化，产生不利于中枢神经系统修复的环境。用我们人类的NPC文化 在严重联合免疫缺陷(SCID)HIV-1脑炎(HIVE)小鼠模型中的系统，本项目 Will模拟HIV-1感染和脑MP的免疫激活并研究中枢炎症的影响 关于神经发生。阐明SDF-1/CXCR4影响神经发生的机制可能会发现新的 治疗HAD和其他神经退行性疾病的治疗策略。相关性： 全球约有4000万人感染艾滋病毒。其中10%-20%的人最终会发展成 艾滋病毒相关性痴呆(HAD)。这项工作将阐明神经发生受到影响的机制。 通过HAD，它可以确定治疗HAD和其他神经退行性变的新治疗策略 精神错乱。

Abstract: Neural progenitor cells (NPC) are present throughout life and replenish neurons and glia (astrocytes and oligodendrocytes) through neurogenesis, a process that requires proper migration, proliferation and differentiation of NPC. Neurogenesis appears to be dysfunctional in neurodegenerative disorders including HIV-1 associated dementia (HAD), Alzheimer's and Parkinson's diseases, where dead or injured neurons are not replaced. HAD is a neurodegenerative disorder where HIV-1-infected and activated brain mononuclear phagocytes (MP; perivascular macrophages and microglia) mediate inflammatory conditions that alter brain homeostasis. We recently demonstrated that HIV-1-infected and activated macrophages inhibit neurogenesis but enhance gliogenesis. We propose this gliogenesis is mediated through brain inflammation attributable to the dysregulation of stromal cell-derived factor 1 (SDF-1). SDF-1 is an endogenous ligand for the chemokine receptor, CXCR4, which is highly expressed on human NPC and mediates NPC migration. Improper SDF-1 and CXCR4 function can affect neural repair by impairing NPC migration. SDF-1 is released in response to glial activation, mediated by inflammatory cytokines from HIV-1-infected and activated MP such as Interleukin one beta (IL-1¿). SDF-1 is elevated in the cerebrospinal fluid of HAD patients. Activated matrix metalloproteinase-2 (MMP-2) is produced by HIV-1 infected and activated MP and cleaves SDF-1 resulting in a neurotoxic fragment. This proposal will examine the role of HIV-1-infected and activated macrophage in brain inflammation and their effects on neurogenesis. We hypothesize HIV-1-infected and immune- activated MP inhibit neuronal differentiation and promote gliogenesis. Specifically, we propose this shift in neurogenesis is dependent upon SDF-1 produced by activated astrocytes. This gliogenesis may be a consequence of modification/degradation of SDF-1 by factors released from HIV-1-infected MP leading to impairment of normal SDF-1/CXCR4 mediated NPC migration, survival, proliferation and differentiation, generating an environment detrimental to CNS repair. Using our human NPC culture system in a severe combined immune deficient (SCID) HIV-1 encephalitis (HIVE) mouse model, this project will mimic HIV-1-infection and immune-activation of brain MP and investigate the effect of CNS inflammation on neurogenesis. Elucidating the mechanisms of SDF-1/CXCR4 influence on neurogenesis may identify new therapeutic strategies for treating HAD and other neurodegenerative disorders. Relevance: Globally, about 40 million people are infected with HIV. 10-20% of these individuals will eventually develop HIV-associated dementia (HAD). This work will elucidate mechanisms through which neurogenesis is affected by HAD, which could identify new therapeutic strategies for treating HAD and other neurodegenerative disorders.