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: 7869501
• 负责人: Jialin Charles Zheng
• 金额: $ 14.45万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7869501
• 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; Figs - dietary; Gelatinase A; Gene Cluster; Generations; Goals; Growth Factor; HIV; HIV encephalitis; HIV-1; Harvest; High Pressure Liquid Chromatography; Hippocampus (Brain); Homeostasis; Human; Human immunodeficiency virus test; Immune; Immunohistochemistry; Impairment; In Situ Hybridization; In Situ Nick-End Labeling; In Vitro; Individual; Infection; Inflammation; Inflammatory; Injection of therapeutic agent; 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; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Staining method; Stains; Stromal Cell-Derived Factor 1; System; Techniques; Testing; Therapeutic; Thick; Thymidine; Time; Tissues; Transcript; Universities; Western Blotting; Work; Wound Healing; abstracting; astrogliosis; brain tissue; cell motility; chemokine; chemokine receptor; cytokine; deprivation; gliogenesis; 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

Abstract: 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-1¿). 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. 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.

摘要： 神经祖细胞（NPC）存在于整个生命过程中，并补充神经元和神经胶质（星形胶质细胞和胶质细胞）。 少突胶质细胞）通过神经发生，这是一个需要适当迁移、增殖和 NPC的分化。神经发生似乎在神经退行性疾病中功能失调，包括 HIV-1相关性痴呆（HAD）、阿尔茨海默病和帕金森病，其中死亡或受伤的神经元被 没有被取代。HAD是一种神经退行性疾病，其中HIV-1感染和激活的脑单核细胞 巨噬细胞（MP;血管周围巨噬细胞和小胶质细胞）介导炎症状态， 体内平衡我们最近证明，HIV-1感染和激活的巨噬细胞抑制神经发生 但增强神经胶质生成。我们认为这种胶质细胞生成是通过脑炎症介导的， 基质细胞衍生因子1（SDF-1）的失调。SDF-1是趋化因子的内源性配体 受体CXCR 4，其在人NPC上高度表达并介导NPC迁移。SDF-1不正确 CXCR 4功能可通过损害NPC迁移影响神经修复。SDF-1的发布是为了回应 胶质细胞活化，由来自HIV-1感染和活化MP的炎性细胞因子介导，如白细胞介素 一个β（IL-1）。SDF-1在HAD患者的脑脊液中升高。活化基质 金属蛋白酶-2（MMP-2）由HIV-1感染和活化的MP产生，并切割SDF-1，导致 神经毒性片段这项建议将研究HIV-1感染和激活的巨噬细胞在 脑炎症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细胞生成。具体来说，我们建议 神经发生的转变依赖于由活化的星形胶质细胞产生的SDF-1。这种神经胶质生成 可能是HIV-1感染者释放的因子修饰/降解SDF-1的结果。 MP导致正常SDF-1/CXCR 4介导的NPC迁移、存活、增殖和凋亡的损害。 分化，产生对CNS修复有害的环境。利用我们人类的NPC文化 系统在严重联合免疫缺陷（SCID）HIV-1脑炎（HIVE）小鼠模型中，该项目 将模拟HIV-1感染和脑MP的免疫激活，并研究CNS炎症的影响 关于神经发生阐明SDF-1/CXCR 4对神经发生的影响机制可能会发现新的 用于治疗HAD和其它神经变性疾病的治疗策略。相关性： 全球约有4 000万人感染艾滋病毒。其中10-20%的人最终会发展成 艾滋病相关性痴呆（HAD）。这项工作将阐明神经发生受到影响的机制 通过HAD，可以确定治疗HAD和其他神经退行性疾病的新治疗策略， 紊乱