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CXCL8-mediated glial cross-talk and neuroprotection in HIV-1 Dementia

HIV-1 痴呆中 CXCL8 介导的神经胶质串扰和神经保护

基本信息

批准号：
8532040
负责人：
Anuja Ghorpade
金额：
$ 34.21万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8532040
关键词：
AIDS Dementia Complex Abbreviations Acquired Immunodeficiency Syndrome Address Age Alzheimer&apos s Disease Anti-Retroviral Agents Apoptosis Area Asthma Astrocytes BCL2 gene Basal Ganglia Biochemical Biological Biology Blood - brain barrier anatomy Brain Bromides CD40 Ligand Cell Survival Cells Central Nervous System Infections Cerebrospinal Fluid Chronic Obstructive Airway Disease Coculture Techniques Complication Consultations DNA Nucleotidylexotransferase Data Data Analyses Dementia Development Digoxigenin Disease Dominant-Negative Mutation Dose Encephalitis Event G Protein-Coupled Receptor Genes G-Protein-Coupled Receptors Genes Glial Fibrillary Acidic Protein HIV HIV encephalitis HIV-1 Highly Active Antiretroviral Therapy Human IL8 gene IL8RA gene IL8RB gene Immune Immune response Impairment In Situ In Situ Nick-End Labeling Infection Inflammation Inflammatory Inflammatory Response Institution Interferons Interleukin 8A Receptor Interleukin-8B Receptor Interleukins Investigation Kinetics Label Laboratories Lactate Dehydrogenase Lead Letters Life Link Literature MAPK3 gene Malignant Neoplasms Mediating Mediator of activation protein Microglia Microscopic Microtubule-Associated Proteins Mitogen-Activated Protein Kinases Molecular Mononuclear N-Methylaspartate Neuraxis Neurocognitive Neurodegenerative Disorders Neuroglia Neurologic Neuronal Injury Neurons Neuropathogenesis Neurotoxins Nuclear Outcome PTPN11 gene Pathway Analysis Pathway interactions Patients Peripheral Blood Mononuclear Cell Phagocytes Phosphatidylinositols Phosphorylation Platelet Activating Factor Play Prevalence Process Production Protein Kinase C Protein Tyrosine Phosphatase Publishing RNA RNA-Directed DNA Polymerase Reactive Oxygen Species Reading Recombinants Recruitment Activity Regulation Regulatory Pathway Research Research Design Role Sampling Scheme Series Signal Pathway Signal Transduction Signaling Molecule Small Interfering RNA Source Specimen Src homology 2 domain-containing, transforming protein 1 Staging Stimulus Synaptophysin System TNFSF5 gene Testing Therapeutic Time Tissue Inhibitor of Metalloproteinases Tissue Sample Tubulin Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha United States Up-Regulation Virus Work astrogliosis autocrine brain tissue cell growth regulation chemokine clinically relevant clinically significant cytokine frontal lobe human MAPK14 protein human NOS2A protein in vivo inhibitor/antagonist insight interest macrophage mild cognitive impairment mitogen-activated protein kinase p38 monocyte mutant neuroinflammation neuronal survival neuroprotection neurotoxicity novel research study response tool

项目摘要

Currently, almost 35 million people live with HIV-1 infection worldwide. HIV-1-associated dementia (HAD) along with mild neurocognitive disorder and asymptomatic neurocognitive impairment comprises the HIV- associated neurocognitive disorder (HAND). Inflammation associated with milder forms of HIV encephalitis shows presence of activated microglia, reactive astrogliosis and neuronal injury in areas of inflammation. A few years ago, we began novel investigations into the potential mechanisms associated with glial activation & their contribution in neuro-AIDS. Primary human glial cells were used in preliminary experiments and CXCL8 was among the key molecules upregulated in activated astrocytes and other neural cells. Importantly, CXCL8 was neuroprotective in cultured human neurons exposed to HIV-1-related neurotoxins. Biological relevance of this observation was further confirmed as HIV-1-infected brain tissues demonstrated greater CXCL8 levels as compared to age-matched controls. We propose that CXCL8 plays a key regulatory role in the intercellular interactions in HIV-1 CNS infection. Microglial infection and activation leads to upregulation of IL-1¿. IL-1¿, a prototypical inflammatory stimulus for astrocytes, enhances CXCL8 production by astrocytes in CNS. CXCL8 further recruits microglia and regulates microglial activation and HIV-1 infection. Taken together, ultimately these events may lead to CXCL8-mediated direct or indirect neuroprotection. To these ends, we will address the following specific questions: How is CXCL8 regulated in activated astrocytes in HAD and what mechanisms are involved? (Aim 1) How does glial CXCL8 regulate microglial recruitment, activation and infection? (Aim 2) How does CXCL8 regulate neuronal survival and/or function during the process of HAD? (Aim 3) In Aim 1, human brain tissue specimens and primary human neural cells will be utilized to delineate CXCL8 profiles and to identify the cellular sources for CXCL8 in HAD. Primary human neural cells will be exposed to HAD-specific stimuli and CXCL8 regulation will be evaluated. The intracellular signaling pathways involved in IL-8 regulation, specifically, NF-¿B, p38MAPK and/or SHP2 will be studied in astrocytes. The role of intercellular interactions between activated astrocytes and microglia via CXCL8-mediated in regulation of microglial activation, recruitment and HIV-1 infection will be evaluated in Aim 2. The mechanisms of CXCL8 neuroprotection and the ensuing signal transduction specifically through Akt/PKB, ERK1/2, Bcl-2 and Bax and the role of TNF receptors in these neuroprotective events will be investigated using primary human neurons in Aim 3. Taken together, the studies proposed in this application will provide novel data about CXCL8-mediated glial cross-talk and neuropathogenesis and lead to novel insights into regulation of glial inflammatory responses that have both basic and clinical significance.

目前，全世界有近3500万人感染艾滋病毒1。HIV-1相关性痴呆（HAD）沿着轻度神经认知障碍和无症状神经认知障碍的是HIV-1，相关神经认知障碍（HAND）。与较温和形式的HIV脑炎相关的炎症显示在炎症区域存在活化的小胶质细胞、反应性星形胶质细胞增生和神经元损伤。几几年前，我们开始了新的研究与神经胶质细胞激活相关的潜在机制，神经艾滋病的贡献。在初步实验中使用原代人神经胶质细胞，并将CXCL 8 在活化的星形胶质细胞和其他神经细胞中上调的关键分子中。重要的是，CXCL 8是对暴露于HIV-1相关神经毒素的培养人类神经元具有神经保护作用。生物相关性进一步证实了这一观察结果，因为HIV-1感染的脑组织显示出更高的CXCL 8水平，与年龄匹配的对照组相比。我们认为CXCL 8在细胞凋亡中起着关键的调节作用。 HIV-1 CNS感染中的细胞间相互作用。小胶质细胞感染和活化导致 IL-1。IL-1是星形胶质细胞的一种典型炎症刺激物，可增强星形胶质细胞产生CXCL 8， CNS。CXCL 8进一步招募小胶质细胞并调节小胶质细胞活化和HIV-1感染。综合起来看，最终，这些事件可导致CXCL 8介导的直接或间接神经保护。为此，我们将解决以下具体问题：HAD中活化的星形胶质细胞中CXCL 8是如何调节的，机制参与？(Aim 1）胶质细胞CXCL 8如何调节小胶质细胞的募集、激活和分化。感染？(Aim 2）CXCL 8如何在HAD过程中调节神经元的存活和/或功能？ (Aim第三条在目标1中，将利用人脑组织标本和原代人类神经细胞来描绘 CXCL 8谱，并确定HAD中CXCL 8的细胞来源。原代人类神经细胞将评估暴露于HAD特异性刺激和CXCL 8调节的小鼠的免疫应答。细胞内信号通路将在星形胶质细胞中研究参与IL-8调节的细胞因子，特别是NF-κ B B、p38 MAPK和/或SHP 2。的作用 CXCL 8介导的活化星形胶质细胞和小胶质细胞之间的细胞间相互作用小胶质细胞活化、募集和HIV-1感染将在目标2中评价。CXCL 8的作用机制神经保护和随后的信号转导，特别是通过Akt/PKB，ERK 1/2，Bcl-2和Bax， TNF受体在这些神经保护事件中的作用将使用原代人神经元进行研究，目标3.总之，本申请中提出的研究将提供关于CXCL 8介导的细胞内毒素的新数据。神经胶质串扰和神经发病机制，并导致新的见解调节神经胶质炎症这些反应具有基础和临床意义。