SDF-1 and neurogenesis in HIV-1 associated dementia

描述（由申请人提供）：神经祖细胞（NPC）存在于整个生命过程中，并通过神经发生补充神经元和神经胶质细胞（星形胶质细胞和少突胶质细胞），这是一个需要NPC适当迁移、增殖和分化的过程。神经发生似乎在神经退行性疾病中功能障碍，包括HIV-1相关痴呆（HAD），阿尔茨海默病和帕金森病，其中死亡或受伤的神经元没有被替换。HAD是一种神经退行性疾病，其中HIV-1感染和激活的脑单核吞噬细胞（MP;血管周围巨噬细胞和小胶质细胞）介导改变脑内稳态的炎性病症。我们最近发现，HIV-1感染和激活的巨噬细胞抑制神经发生，但增强胶质细胞的生成。我们提出这种胶质细胞生成是通过脑炎症介导的，可归因于基质细胞衍生因子1（SDF-1）的失调。SDF-1是趋化因子受体CXCR 4的内源性配体，CXCR 4在人NPC上高度表达并介导NPC迁移。不当的SDF-1和CXCR 4功能可以通过损害NPC迁移来影响神经修复。SDF-1在神经胶质细胞活化时释放，由HIV-1感染和活化MP的炎性细胞因子如白细胞介素1 β（IL-12）介导。SDF-1在HAD患者的脑脊液中升高。活化的基质金属蛋白酶-2（MMP-2）由HIV-1感染和活化的MP产生，并切割SDF-1，产生神经毒性片段。这项建议将研究HIV-1感染和激活的巨噬细胞在脑炎症中的作用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，我们提出这种神经发生的转变依赖于活化的星形胶质细胞产生的SDF-1。这种胶质细胞生成可能是由HIV-1感染的MP释放的因子修饰/降解SDF-1的结果，导致正常SDF-1/CXCR 4介导的NPC迁移、存活、增殖和分化受损，产生对CNS修复有害的环境。利用我们的人NPC培养系统在严重联合免疫缺陷（SCID）HIV-1脑炎（HIVE）小鼠模型中，本项目将模拟HIV-1感染和脑MP的免疫激活，并研究CNS炎症对神经发生的影响。阐明SDF-1/CXCR 4影响神经发生的机制可能会为治疗HAD和其他神经退行性疾病找到新的治疗策略。全球约有4000万人感染艾滋病毒。这些人中有10-20%最终会发展为艾滋病毒相关性痴呆（HAD）。这项工作将阐明神经发生受HAD影响的机制，这可以确定治疗HAD和其他神经退行性疾病的新治疗策略。

DESCRIPTION (provided by applicant): 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-12). 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. PUBLIC HEALTH 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.