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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 神经祖细胞（NPC）对于维持中枢神经系统稳态至关重要。 这些细胞在一生中持续存在，并根据需要通过称为神经发生的过程来补充神经元，星形胶质细胞和少突胶质细胞。 在神经退行性疾病中，由于未替代死亡或受伤的神经元，星形胶质细胞和少突胶质细胞，因此此过程似乎是功能失调的。 艾滋病毒相关的痴呆症（HAD）是引起重大兴趣的这些疾病之一。 最近，我们证明了CXCR4是HIV-1的重要共受体，在人NPC上比其他趋化因子受体更高表达，并且与下游信号系统偶联。响应神经元损伤和星形胶质细胞激活而释放的固有CXCR4配体，基质细胞衍生的因子1（SDF-1）在HAT患者的脑脊髓液中也升高了与没有神经疾病的受试者相比。最近的研究还表明，SDF-1被活化基质金属蛋白酶-2（MMP-2）裂解以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HAS中起着核心作用。 神经发生是一个新兴领域，其在HAT中的作用很少。 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.使用新开发的人类NPC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，并在体外测定中模仿脑MP激活和先天性中枢神经系统的免疫反应，以检查SDF-1调节的机制。通过阐明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为治疗的新治疗策略开放，不仅具有其他神经退行性疾病。