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 万人患有 HIV-1 相关痴呆症 (HAD)。与轻度神经认知障碍和无症状神经认知障碍一起包括 HIV- 相关神经认知障碍 (HAND) 与较轻形式的 HIV 脑炎相关的炎症。显示一些炎症区域存在激活的小胶质细胞、反应性星形胶质细胞增生和神经元损伤。几年前，我们开始对与神经胶质激活及其相关的潜在机制进行新的研究在初步实验中使用了原代人类神经胶质细胞，CXCL8 在神经艾滋病中的贡献。重要的是，CXCL8 是在激活的星形胶质细胞和其他神经细胞中上调的关键分子之一。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。进一步证实了这一观察结果，因为 HIV-1 感染的脑组织表现出更高的 CXCL8 水平与年龄匹配的对照相比，我们认为 CXCL8 在其中发挥着关键的调节作用。 HIV-1 CNS 感染中的细胞间相互作用导致小胶质细胞感染和激活上调。 IL-1?? .IL-1¿是一种典型的星形胶质细胞炎症刺激物，可增强星形胶质细胞的 CXCL8 产生 CNS。CXCL8 进一步招募小胶质细胞并调节小胶质细胞激活和 HIV-1 感染。最终，这些事件可能导致 CXCL8 介导的直接或间接神经保护作用。为此，我们将进行研究。解决以下具体问题：HAD 中激活的星形胶质细胞中的 CXCL8 是如何受到调节的？涉及机制？（目标 1）神经胶质细胞 CXCL8 如何调节小胶质细胞的招募、激活和（目标 2）CXCL8 在 HAD 过程中如何调节神经元存活和/或功能？（目标 3）在目标1中，将利用人类脑组织标本和原代人类神经细胞来描绘 CXCL8 概况并鉴定 HAD 中 CXCL8 的细胞来源。将评估暴露于 HAD 特异性刺激和 CXCL8 调节的细胞内信号通路。参与 IL-8 调节，特别是 NF-¿ B、将研究p38MAPK和/或SHP2在星形胶质细胞中的作用。活化的星形胶质细胞和小胶质细胞之间通过 CXCL8 介导的细胞间相互作用小胶质细胞激活、招募和 HIV-1 感染将在目标 2 中进行评估。 CXCL8 的机制神经保护以及随后的信号转导，特别是通过 Akt/PKB、ERK1/2、Bcl-2 和 Bax 进行将使用原代人类神经元来研究 TNF 受体在这些神经保护事件中的作用目标 3. 总而言之，本申请中提出的研究将提供有关 CXCL8 介导的新数据神经胶质细胞串扰和神经发病机制，并导致对神经胶质炎症调节的新见解具有基础和临床意义的反应。