CELLULAR MECHANISMS FOR HIV 1 INDUCED NEURONAL INJURY

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。神经前体细胞（NPC）是维持CNS稳态的关键。这些细胞在整个生命中持续存在，并通过称为神经发生的过程根据需要补充神经元、星形胶质细胞和少突胶质细胞。在神经退行性疾病，如艾滋病毒相关性痴呆（HAD），这一过程似乎是功能失调。最近，我们证明了CXCR 4，一个重要的辅助受体的HIV-1，更高地表达在人类NPC和耦合到下游信号系统。内在CXCR 4配体，基质细胞衍生因子1（SDF-1），释放响应神经元损伤和星形胶质细胞活化也升高HAD患者的脑脊液相比，感染的受试者没有神经系统疾病。最近的研究还表明，SDF-1被活化的基质金属蛋白酶-2（MMP-2）切割，形成高度神经毒性的SDF-1（5-67）。MMP-2也在HIV-1感染的单核吞噬细胞（MP）上高度表达，其在HAD中起核心作用。该提案检验了以下假设：虽然活化的星形胶质细胞和受损的神经元产生促进神经发生的升高水平的SDF-1，但由HIV-1感染的MP释放的酶对SDF-1的蛋白水解可能导致SDF-1/CXCR 4介导的神经原性反应受损，并证明对CNS修复有害。利用新开发的人NPC培养系统，我们建议研究SDF-1在神经发生中的作用（生产，修饰和功能）。我们将使用分子操作，包括基因沉默，并在体外试验，模拟脑MP激活和先天性中枢神经系统免疫反应，发生在HAD，检查SDF-1的调节机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Neural progenitor cells (NPC) are critical for maintenance of CNS homeostasis. These cells persist throughout life and replenish neurons, astrocytes and oligodendrocytes as needed through a process referred to as neurogenesis. In neurodegenerative disorders such as HIV associated dementia (HAD), this process appears to be dysfunctional. Recently, we demonstrated that CXCR4, an important co-receptor for HIV-1, was more highly expressed on human NPC and was coupled to downstream signaling systems. The intrinsic CXCR4 ligand, stromal cell-derived factor 1 (SDF-1), released in response to neuronal injury and astrocyte activation was also elevated in cerebral spinal fluids of HAD patients compared to infected subjects without neurological disorders. Recent studies have also shown that SDF-1 is cleaved by activated matrix metalloproteinase-2 (MMP-2) to form the highly neurotoxic SDF-1 (5-67). MMP-2 is also highly expressed on HIV-1-infected mononuclear phagocytes (MP), which play a central role in HAD. This proposal examines the hypothesis that while activated astrocytes and injured neurons produce elevated levels of SDF-1 that promote neurogenesis, proteolysis of SDF-1 by enzymes released from HIV-1-infected MP could lead to an impairment of SDF-1/CXCR4 mediated neurogenic responses and prove detrimental to CNS repair. Using a newly developed human NPC culture system, we propose to study the role of SDF-1 (production, modification and function) in neurogenesis. We will use molecular manipulations, including gene silencing, and in vitro assays that mimic brain MP activation and innate CNS immune responses that occur in HAD, to examine the mechanisms of SDF-1 regulation.