SDF-1 and neurogenesis in HIV-1 associated dementia

描述(申请人提供)：神经前体细胞(NPC)存在于生命中，通过神经发生补充神经元和神经胶质(星形胶质细胞和少突胶质细胞)，这一过程需要NPC适当的迁移、增殖和分化。在包括HIV-1相关性痴呆(HAD)、阿尔茨海默氏症和帕金森氏症在内的神经退行性疾病中，神经发生似乎是功能失调的，在这些疾病中，死亡或受伤的神经元无法被替换。HAD是一种神经退行性疾病，HIV-1感染并激活的脑单核巨噬细胞(MP；血管周围巨噬细胞和小胶质细胞)介导的炎症条件改变了大脑的动态平衡。我们最近证实，HIV-1感染和激活的巨噬细胞抑制神经发生，但促进神经发生。我们认为，这种胶质形成是通过基质细胞衍生因子1(SDF-1)的失调引起的脑部炎症来调节的。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，并介导鼻咽癌的迁移。SDF-1和CXCR4功能异常可能通过损害鼻咽癌的迁移而影响神经修复。SDF-1是由HIV-1感染和激活的MP产生的炎性细胞因子(如白介素1-β(IL-12))介导的神经胶质细胞激活而释放的。HAD患者脑脊液中SDF-1水平升高。活化的基质金属蛋白酶-2(MMP2)是由HIV-1感染并激活的MP产生的，可裂解SDF-1，产生神经毒性片段。这项提案将研究HIV-1感染和激活的巨噬细胞在脑部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，促进神经胶质形成。具体地说，我们认为神经发生的这种转变依赖于激活的星形胶质细胞产生的SDF-1。这种胶质形成可能是HIV-1感染的MP释放的因子修饰/降解SDF-1的结果，导致正常的SDF-1/CXCR4介导的鼻咽癌迁移、存活、增殖和分化受到损害，从而产生了不利于中枢神经系统修复的环境。利用我们建立的人鼻咽癌培养系统，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寻找新的治疗策略。在全球范围内，约有4000万人感染艾滋病毒。这些人中有10%-20%最终会患上艾滋病毒相关性痴呆(HAD)。这项工作将阐明HAD影响神经发生的机制，从而为HAD和其他神经退行性疾病的治疗找到新的治疗策略。

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.