CELLULAR MECHANISMS FOR HIV 1 INDUCED NEURONAL INJURY

HIV 1 引起的神经元损伤的细胞机制

• 批准号: 7959385
• 负责人: Jialin Charles Zheng
• 金额: $ 6.69万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959385
• 关键词: AIDS Dementia Complex; Astrocytes; Brain; CXCR4 gene; Cell Culture System; Cells; Cerebrospinal Fluid; Cerebrum; Cleaved cell; Computer Retrieval of Information on Scientific Projects Database; Coupled; Disease; Enzymes; Funding; Gelatinase A; Gene Silencing; Grant; HIV; HIV-1; Homeostasis; Human; Immune response; Impairment; Institution; Knowledge; Lead; Life; Ligands; Maintenance; Mediating; Modification; Molecular; Mononuclear; Nebraska; Neurodegenerative Disorders; Neuronal Injury; Neurons; Oligodendroglia; Patients; Phagocytes; Play; Process; Production; Proteolysis; Regulation; Research; Research Personnel; Resources; Role; Signal Transduction; Source; Stromal Cell-Derived Factor 1; System; United States National Institutes of Health; chemokine receptor; in vitro Assay; injured; interest; nerve stem cell; nervous system disorder; neurogenesis; neurotoxic; novel therapeutics; receptor; repaired; response; virology

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 神经祖细胞 (NPC) 对于维持中枢神经系统稳态至关重要。 这些细胞终生持续存在，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，这个过程似乎是功能失调的，因为死亡或受损的神经元、星形胶质细胞和少突胶质细胞没有被替换。 HIV相关性痴呆（HAD）是引起人们极大兴趣的疾病之一。 最近，我们证明CXCR4是HIV-1的重要辅助受体，在人类NPC上比其他趋化因子受体表达更高，并且与下游信号系统偶联。与没有神经系统疾病的感染者相比，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) 也有所升高。最近的研究还表明，SDF-1 被活化的基质金属蛋白酶-2 (MMP-2) 裂解，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) 上也高表达，在 HAD 中发挥核心作用。 神经发生是一个新兴领域，人们对它在 HAD 中的作用知之甚少。 该提案检验了这样的假设：虽然激活的星形胶质细胞和受损的神经元产生升高水平的 SDF-1，从而促进神经发生，但 HIV-1 感染的 MP 释放的酶对 SDF-1 的蛋白水解可能会导致 SDF-1/CXCR4 介导的神经源性反应受损，并证明不利于 CNS 修复。使用新开发的人类 NPC 培养系统，我们建议研究 SDF-1（产生、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 中发生的脑 MP 激活和先天 CNS 免疫反应的体外测定，来检查 SDF-1 调节机制。从阐明 SDF-1/CXCR4 在神经发生中相互作用的机制中获得的知识可能会开辟新的治疗策略，不仅可以治疗 HAD，还可以治疗其他神经退行性疾病。