SDF-1 and neurogenesis in HIV-1 associated dementia

描述（由申请人提供）：神经祖细胞（Neural progenitor cells， NPC）存在于整个生命过程中，通过神经发生（neurogenesis）补充神经元和胶质细胞（星形胶质细胞和少突胶质细胞），这一过程需要NPC的适当迁移、增殖和分化。神经发生在包括HIV-1相关痴呆（HAD）、阿尔茨海默病和帕金森病在内的神经退行性疾病中似乎是功能失调的，在这些疾病中，死亡或受伤的神经元不能被替换。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）介导炎症，改变脑内稳态。我们最近证明hiv -1感染和激活的巨噬细胞抑制神经发生，但增强胶质细胞发生。我们提出这种胶质细胞形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CXCR4的内源性配体，在人鼻咽癌上高表达并介导鼻咽癌迁移。不适当的SDF-1和CXCR4功能可通过损害鼻咽癌迁移而影响神经修复。SDF-1是在受hiv -1感染和活化的MP（如白细胞介素-1 β (IL-12)）的炎症细胞因子介导的胶质细胞激活下释放的。HAD患者脑脊液中SDF-1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。本研究将探讨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形成。具体来说，我们认为这种神经发生的转变依赖于活化星形胶质细胞产生的SDF-1。这种胶质细胞形成可能是由hiv -1感染的MP释放的因子修饰/降解SDF-1的结果，导致SDF-1/CXCR4介导的正常NPC迁移、存活、增殖和分化受损，从而产生不利于中枢神经系统修复的环境。本项目将利用我们的人类NPC培养系统在严重联合免疫缺陷（SCID） HIV-1脑炎（HIVE）小鼠模型中模拟HIV-1感染和脑MP的免疫激活，并研究中枢神经系统炎症对神经发生的影响。阐明SDF-1/CXCR4影响神经发生的机制可能为治疗HAD和其他神经退行性疾病找到新的治疗策略。全球约有4 000万人感染艾滋病毒。其中10-20%的人最终会发展为艾滋病毒相关痴呆（HAD）。这项工作将阐明HAD影响神经发生的机制，为HAD和其他神经退行性疾病的治疗提供新的治疗策略。

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.