SDF-1 and neurogenesis in HIV-1 associated dementia

SDF-1 和 HIV-1 相关痴呆的神经发生

基本信息

批准号：
8266024
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
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8266024
关键词：
AIDS Dementia Complex Acute Affect Alzheimer&apos 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 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 tissue repair transcription factor treatment effect

项目摘要

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）在整个生命中存在，并通过神经发生补充神经元和神经元（星形胶质细胞和少突胶质细胞），这一过程需要适当的NPC迁移，增殖和分化。神经发生似乎在神经退行性疾病中功能失调，包括HIV-1相关痴呆症（HAD），阿尔茨海默氏症和帕金森氏病，那里未替代死亡或受伤的神经元。有神经退行性疾病，其中HIV-1感染和激活的脑单核吞噬细胞（MP；血管周围巨噬细胞和小胶质细胞）介导改变了脑稳态的炎症状况。我们最近证明，HIV-1感染和激活的巨噬细胞抑制神经发生，但增强了神经胶质发生。我们提出，这种神经胶质发生是通过脑部炎症介导的，归因于基质细胞衍生因子1（SDF-1）的失调。 SDF-1是趋化因子受体CXCR4的内源配体，该配体在人NPC上高度表达并介导NPC迁移。 SDF-1和CXCR4功能不当会通过损害NPC迁移而影响神经修复。 SDF-1响应于神经胶质激活而释放，这是由HIV-1感染和活化的MP（例如白介素ONE BETA）（IL-12）的炎性细胞因子介导的。在HAT患者的脑脊液中，SDF-1升高。活性基质金属蛋白酶-2（MMP-2）是由HIV-1感染并活化的MP产生的，裂解SDF-1导致神经毒性片段。该建议将研究HIV-1感染和激活的巨噬细胞在脑炎症中的作用及其对神经发生的影响。我们假设HIV-1感染和免疫活化的MP抑制神经元分化并促进神经胶质发生。具体而言，我们提出神经发生的这种转变取决于活化的星形胶质细胞产生的SDF-1。这种神经胶质发生可能是由HIV-1感染的MP释放的因素对SDF-1进行了修饰/降解的结果，从而导致正常SDF-1/CXCR4介导的NPC迁移，生存，增殖和分化，从而损害了CNS维修的环境。在严重的免疫缺陷（SCID）HIV-1脑炎（HIVE）小鼠模型中，使用我们的人类NPC培养系统，该项目将模仿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对神经发生的影响的机制可能确定治疗患者和其他神经退行性疾病的新治疗策略。全球公共卫生相关，大约有4000万人感染了艾滋病毒。这些人中有10-20％最终将发展与HIV相关的痴呆（HAT）。这项工作将阐明神经发生受HAT的影响的机制，该机制可以鉴定出用于治疗HAT和其他神经退行性疾病的新治疗策略。