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3500万人生活在HIV-1感染中。 HIV-1相关痴呆（HAD）以及轻度神经认知障碍和不对称的神经认知障碍，包括HIV- 相关的神经认知障碍（手）。与米勒形式的HIV脑炎相关的炎症表明炎症区域中存在活化的小胶质细胞，反应性星形胶质细胞增多症和神经元损伤。几个几年前，我们开始对与神经胶质激活相关的潜在机制进行新颖的研究神经辅助的贡献。原代人神经胶质细胞用于初步实验，CXCL8为在活化的星形胶质细胞和其他中性细胞中更新的关键分子中。重要的是，CXCL8是暴露于HIV-1相关神经毒素的培养的人神经元中的神经保护作用。生物学相关性观察进一步得到证实，因为HIV-1感染的脑组织表现出更大的CXCL8水平与年龄匹配的对照相比。我们建议CXCL8在 HIV-1 CNS感染中的细胞间相互作用。小胶质细胞感染和激活导致上调 IL-1。 IL-1，是一种用于星形胶质细胞的典型炎症刺激，可增强星形胶质细胞的CXCL8产生 CNS。 CXCL8进一步募集小胶质细胞并调节小胶质细胞激活和HIV-1感染。在一起，最终，这些事件可能导致CXCL8介导的直接或间接神经保护。到这些目的，我们将解决以下特定问题：在激活的星形胶质细胞中，CXCL8如何调节涉及机制吗？（AIM 1）Glial CXCL8如何调节小胶质募集，激活和感染？（AIM 2）CXCL8在HAD过程中如何调节神经元存活和/或功能？（目标3）在AIM 1中，将利用人脑组织标本和原代人神经细胞来描述 CXCL8概况并确定CXCL8 HAD的细胞源。原发性人类神经细胞将是将评估暴露于具有特异性刺激和CXCL8调节的情况下。细胞内信号通路参与IL-8调节，具体来说，NF-€，P38MAPK和/或SHP2将在星形胶质细胞中研究。的作用激活的星形胶质细胞与小胶质细胞之间的细胞间相互作用通过CXCL8介导的调节小胶质激活，募集和HIV-1感染将在AIM 2中评估。CXCL8的机制神经保护和随之而来的信号转导特别是通过AKT/PKB，ERK1/2，BCL-2和BAX，以及 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在目的3。总的来说，本应用程序中提出的研究将提供有关CXCL8介导的新数据神经胶质串扰和神经病发生，并导致对神经胶质炎症调节的新见解具有基本和临床意义的反应。