SDF-1 and neurogenesis in HIV-1 associated dementia

SDF-1 和 HIV-1 相关痴呆的神经发生

• 批准号: 8026004
• 负责人: Jialin Charles Zheng
• 金额: $ 36.02万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8026004
• 关键词: AIDS Dementia Complex; Acute; Affect; Alzheimer' s Disease; Animals; Apoptosis; Area; Astrocytes; Autopsy; Basal Ganglia; Biological Assay; Brain; CXCR4 Receptors; CXCR4 gene; Cathepsin G; Cell Culture System; Cell Cycle; Cell Differentiation process; Cell Proliferation; Cell Survival; Cell physiology; Cells; Central Nervous System Viral Diseases; Cerebrospinal Fluid; Chemotactic Factors; Chemotaxis; Chronic; Cleaved cell; Coculture Techniques; Confocal Microscopy; Cyclin D1; Data; Dementia; Detection; Development; Disease; Encephalitis; Environment; Enzymes; Event; Gelatinase A; Gene Cluster; Generations; Goals; Growth Factor; HIV; HIV-1; Harvest; Health; High Pressure Liquid Chromatography; Hippocampus (Brain); Homeostasis; Human; Immune; Immunohistochemistry; Impairment; In Situ Hybridization; In Situ Nick-End Labeling; In Vitro; Individual; Infection; Inflammation; Inflammatory; Injection of therapeutic agent; Interleukin-12; Interleukins; Investigation; Kinetics; Knock-out; Knockout Mice; Label; Leukocyte Elastase; Life; Ligands; Lipopolysaccharides; Matrix Metalloproteinases; Measurement; Mediating; Medical center; Methods; Microglia; Mitogen-Activated Protein Kinases; Modality; Modeling; Modification; Monitor; Mononuclear; Multiple Sclerosis; Mus; Nebraska; Nervous system structure; Neurodegenerative Disorders; Neuroglia; Neuronal Differentiation; Neuronal Injury; Neurons; Neuropathogenesis; Neurovirology; Oligodendroglia; Parkinson Disease; Pathology; Pathway interactions; Patients; Peptides; Phagocytes; Phase; Process; Production; Property; Proteins; RNA; Recombinants; Regulation; Research; Resources; Reverse Transcriptase Polymerase Chain Reaction; Rodent Model; Role; SCID Mice; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Staining method; Stains; Stromal Cell-Derived Factor 1; System; TNF gene; Techniques; Testing; Therapeutic; Thick; Thymidine; Time; Tissues; Transcript; Universities; Western Blotting; Work; Wound Healing; astrogliosis; brain tissue; cell motility; chemokine; chemokine receptor; cytokine; deprivation; gliogenesis; immune activation; immunocytochemistry; in vivo; injured; injury and repair; liquid chromatography mass spectrometry; macrophage; migration; monocyte; mouse model; nerve stem cell; neurogenesis; neurotoxic; novel therapeutics; overexpression; prevent; relating to nervous system; release factor; repaired; research study; response; single photon emission computed tomography; transcription factor; treatment effect

DESCRIPTION (provided by applicant): Neural progenitor cells (NPC) are present throughout life and replenish neurons and glia (astrocytes and oligodendrocytes) through neurogenesis, a process that requires proper migration, proliferation and differentiation of NPC. Neurogenesis appears to be dysfunctional in neurodegenerative disorders including HIV-1 associated dementia (HAD), Alzheimer's and Parkinson's diseases, where dead or injured neurons are not replaced. HAD is a neurodegenerative disorder where HIV-1-infected and activated brain mononuclear phagocytes (MP; perivascular macrophages and microglia) mediate inflammatory conditions that alter brain homeostasis. We recently demonstrated that HIV-1-infected and activated macrophages inhibit neurogenesis but enhance gliogenesis. We propose this gliogenesis is mediated through brain inflammation attributable to the dysregulation of stromal cell-derived factor 1 (SDF-1). SDF-1 is an endogenous ligand for the chemokine receptor, CXCR4, which is highly expressed on human NPC and mediates NPC migration. Improper SDF-1 and CXCR4 function can affect neural repair by impairing NPC migration. SDF-1 is released in response to glial activation, mediated by inflammatory cytokines from HIV-1-infected and activated MP such as Interleukin one beta (IL-12). SDF-1 is elevated in the cerebrospinal fluid of HAD patients. Activated matrix metalloproteinase-2 (MMP-2) is produced by HIV-1 infected and activated MP and cleaves SDF-1 resulting in a neurotoxic fragment. This proposal will examine the role of HIV-1-infected and activated macrophage in brain inflammation and their effects on neurogenesis. We hypothesize HIV-1-infected and immune- activated MP inhibit neuronal differentiation and promote gliogenesis. Specifically, we propose this shift in neurogenesis is dependent upon SDF-1 produced by activated astrocytes. This gliogenesis may be a consequence of modification/degradation of SDF-1 by factors released from HIV-1-infected MP leading to impairment of normal SDF-1/CXCR4 mediated NPC migration, survival, proliferation and differentiation, generating an environment detrimental to CNS repair. Using our human NPC culture system in a severe combined immune deficient (SCID) HIV-1 encephalitis (HIVE) mouse model, this project will mimic HIV-1-infection and immune-activation of brain MP and investigate the effect of CNS inflammation on neurogenesis. Elucidating the mechanisms of SDF-1/CXCR4 influence on neurogenesis may identify new therapeutic strategies for treating HAD and other neurodegenerative disorders. PUBLIC HEALTH RELEVANCE Globally, about 40 million people are infected with HIV. 10-20% of these individuals will eventually develop HIV-associated dementia (HAD). This work will elucidate mechanisms through which neurogenesis is affected by HAD, which could identify new therapeutic strategies for treating HAD and other neurodegenerative disorders.

描述（由申请人提供）：神经祖细胞 (NPC) 存在于整个生命周期，并通过神经发生补充神经元和神经胶质细胞（星形胶质细胞和少突胶质细胞），神经发生是一个需要 NPC 适当迁移、增殖和分化的过程。在神经退行性疾病中，神经发生似乎出现功能障碍，包括 HIV-1 相关痴呆 (HAD)、阿尔茨海默病和帕金森病，这些疾病中死亡或受损的神经元没有被替换。 HAD 是一种神经退行性疾病，其中 HIV-1 感染并激活的大脑单核吞噬细胞（MP；血管周围巨噬细胞和小胶质细胞）介导炎症状况，从而改变大脑稳态。我们最近证明，HIV-1 感染并激活的巨噬细胞会抑制神经发生，但会增强胶质细胞生成。我们认为这种胶质生成是通过基质细胞衍生因子 1 (SDF-1) 失调引起的脑炎症介导的。 SDF-1 是趋化因子受体 CXCR4 的内源性配体，CXCR4 在人类 NPC 上高表达并介导 NPC 迁移。 SDF-1 和 CXCR4 功能不当会通过损害 NPC 迁移来影响神经修复。 SDF-1 响应神经胶质细胞激活而释放，由来自 HIV-1 感染和激活的 MP 的炎性细胞因子（例如白细胞介素 1 β (IL-12)）介导。 HAD 患者脑脊液中 SDF-1 升高。激活的基质金属蛋白酶-2 (MMP-2) 由 HIV-1 感染并激活的 MP 产生，并裂解 SDF-1，产生神经毒性片段。该提案将研究 HIV-1 感染和激活的巨噬细胞在脑部炎症中的作用及其对神经发生的影响。我们假设 HIV-1 感染和免疫激活的 MP 抑制神经元分化并促进胶质生成。具体来说，我们认为神经发生的这种转变取决于激活的星形胶质细胞产生的 SDF-1。这种胶质生成可能是 HIV-1 感染的 MP 释放的因子对 SDF-1 进行修饰/降解的结果，导致正常 SDF-1/CXCR4 介导的 NPC 迁移、存活、增殖和分化受损，产生不利于 CNS 修复的环境。该项目将在严重联合免疫缺陷 (SCID) HIV-1 脑炎 (HIVE) 小鼠模型中使用我们的人类 NPC 培养系统，模拟 HIV-1 感染和脑 MP 的免疫激活，并研究中枢神经系统炎症对神经发生的影响。阐明 SDF-1/CXCR4 对神经发生的影响机制可能会确定治疗 HAD 和其他神经退行性疾病的新治疗策略。公共卫生相关性 全球约有 4000 万人感染艾滋病毒。其中 10-20% 的人最终会患上 HIV 相关痴呆 (HAD)。这项工作将阐明 HAD 影响神经发生的机制，从而可以确定治疗 HAD 和其他神经退行性疾病的新治疗策略。