CELLULAR MECHANISMS FOR HIV 1 INDUCED NEURONAL INJURY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 神经前体细胞(NPC)是维持中枢神经系统内环境稳定的关键。这些细胞在生命中持续存在，并根据需要通过被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，这一过程似乎是功能失调的，因为死亡或受伤的神经元、星形胶质细胞和少突胶质细胞没有被取代。人类免疫缺陷病毒相关性痴呆(HAD)就是其中一种引起广泛关注的疾病。最近，我们证明了HIV-1的重要辅助受体CXCR4在人鼻咽癌组织中的表达高于其他趋化因子受体，并与下游信号系统偶联。HAD患者脑脊液中固有的CXCR4配体--基质细胞衍生因子-1(SDF-1)在神经元损伤和星形胶质细胞激活反应中的释放也高于感染的非神经系统疾病患者。最近的研究还表明，SDF-1被激活的基质金属蛋白酶-2(MMP2)裂解，形成高度神经毒性的SDF-1(5-67)。在HIV-1感染的单核巨噬细胞(MP)上也高表达MMP2，而MP在HAD中起着核心作用。神经发生是一个新兴领域，人们对其在HAD中的作用知之甚少。这一建议验证了一种假设，即当激活的星形胶质细胞和受损的神经元产生高水平的SDF-1促进神经发生时，由HIV-1感染的MP释放的酶对SDF-1的蛋白分解可能导致SDF-1/CXCR4介导的神经源性反应受损，并被证明对中枢神经系统的修复不利。利用一个新开发的人鼻咽癌培养系统，我们建议研究SDF-1(生产、修饰和功能)在神经发生中的作用。我们将使用分子操作，包括基因沉默，以及模拟HAD中脑MP激活和先天CNS免疫反应的体外实验，来研究SDF-1的调节机制。通过阐明SDF-1/CXCR4在神经发生中相互作用的机制所获得的知识，可能为不仅治疗HAD而且治疗其他神经退行性疾病开辟新的治疗策略。

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, this process appears to be dysfunctional since dead or injured neurons, astrocytes and oligodendrocytes are not replaced. HIV associated dementia (HAD) is one of these disorders that has aroused significant interest. Recently, we demonstrated that CXCR4, an important co-receptor for HIV-1, was more highly expressed on human NPC than other chemokine receptors, 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. Neurogenesis is an emerging field and its role in HAD is poorly understood. 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. The knowledge gained from elucidating the mechanisms by which SDF-1/CXCR4 interact in neurogenesis may open up new therapeutic strategies for treating not only HAD but other neurodegenerative disorders.