SDF-1 and neurogenesis in HIV-1 associated dementia

摘要： 神经祖细胞（NPC）存在于整个生命过程中，并补充神经元和神经胶质（星形胶质细胞和胶质细胞）。 少突胶质细胞）通过神经发生，这是一个需要适当迁移、增殖和 NPC的分化。神经发生似乎在神经退行性疾病中功能失调，包括 HIV-1相关性痴呆（HAD）、阿尔茨海默病和帕金森病，其中死亡或受伤的神经元被 没有被取代。HAD是一种神经退行性疾病，其中HIV-1感染和激活的脑单核细胞 巨噬细胞（MP;血管周围巨噬细胞和小胶质细胞）介导炎症状态， 体内平衡我们最近证明，HIV-1感染和激活的巨噬细胞抑制神经发生 但增强神经胶质生成。我们认为这种胶质细胞生成是通过脑炎症介导的， 基质细胞衍生因子1（SDF-1）的失调。SDF-1是趋化因子的内源性配体 受体CXCR 4，其在人NPC上高度表达并介导NPC迁移。SDF-1不正确 CXCR 4功能可通过损害NPC迁移影响神经修复。SDF-1的发布是为了回应 胶质细胞活化，由来自HIV-1感染和活化MP的炎性细胞因子介导，如白细胞介素 一个β（IL-1）。SDF-1在HAD患者的脑脊液中升高。活化基质 金属蛋白酶-2（MMP-2）由HIV-1感染和活化的MP产生，并切割SDF-1，导致 神经毒性片段这项建议将研究HIV-1感染和激活的巨噬细胞在 脑炎症及其对神经发生的影响。我们假设HIV-1感染和免疫- 激活的MP抑制神经元分化并促进胶质细胞生成。具体来说，我们建议 神经发生的转变依赖于由活化的星形胶质细胞产生的SDF-1。这种神经胶质生成 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/CXCR 4介导的NPC迁移、存活、增殖和凋亡的损害。 分化，产生对CNS修复有害的环境。利用我们人类的NPC文化 系统在严重联合免疫缺陷（SCID）HIV-1脑炎（HIVE）小鼠模型中，该项目 将模拟HIV-1感染和脑MP的免疫激活，并研究CNS炎症的影响 关于神经发生阐明SDF-1/CXCR 4对神经发生的影响机制可能会发现新的 用于治疗HAD和其它神经变性疾病的治疗策略。相关性： 全球约有4 000万人感染艾滋病毒。其中10-20%的人最终会发展成 艾滋病相关性痴呆（HAD）。这项工作将阐明神经发生受到影响的机制 通过HAD，可以确定治疗HAD和其他神经退行性疾病的新治疗策略， 紊乱

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.