CELLULAR MECHANISMS FOR HIV 1 INDUCED NEURONAL INJURY

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。神经祖细胞（NPC）对维持中枢神经系统稳态至关重要。这些细胞在整个生命过程中持续存在，并根据需要通过称为神经发生的过程补充神经元，星形胶质细胞和少突胶质细胞。在神经退行性疾病中，如HIV相关痴呆（HAD），这一过程似乎是功能失调的。最近，我们证明了CXCR4是HIV-1重要的共受体，在人鼻咽癌上表达更高，并与下游信号系统偶联。与没有神经系统疾病的感染受试者相比，HAD患者脑脊液中因神经元损伤和星形胶质细胞激活而释放的内在CXCR4配体基质细胞衍生因子1 （SDF-1）也升高。最近的研究也表明，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在hiv -1感染的单核吞噬细胞（MP）上也高度表达，在HAD中起核心作用。本研究提出了一种假说，即激活的星形胶质细胞和损伤的神经元产生升高的SDF-1水平，促进神经发生，但hiv -1感染的MP释放的酶对SDF-1的蛋白水解可能导致SDF-1/CXCR4介导的神经发生反应受损，并证明对中枢神经系统修复有害。利用新建立的人鼻咽癌培养系统，我们拟研究SDF-1在神经发生中的作用（产生、修饰和功能）。我们将使用分子操作，包括基因沉默，以及模拟HAD中发生的脑MP激活和先天CNS免疫反应的体外实验，来研究SDF-1调节的机制。

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.