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：
7758688
负责人：
Anuja Ghorpade
金额：
$ 36万
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 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7758688
关键词：
AIDS Dementia Complex Abbreviations Acquired Immunodeficiency Syndrome Address Age Alzheimer&apos s Disease Anti-Retroviral Agents Apoptosis Area Asthma Astrocytes 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 Extracellular Signal Regulated Kinases 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-12 Interleukin-8B Receptor Interleukins Investigation Kinetics Label Laboratories Lactate Dehydrogenase Lead Letters Life Link Literature Malignant Neoplasms Mediating Mediator of activation protein Microglia Microscopic Microtubule-Associated Proteins Mitogen-Activated Protein Kinase 3 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-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 Tumor Necrosis Factors United States Up-Regulation Virus Work astrogliosis autocrine brain tissue cell growth regulation cell type chemokine clinically relevant clinically significant cytokine frontal lobe human MAPK14 protein human NOS2A protein in vivo inhibitor/antagonist insight interest macrophage mild neurocognitive impairment mitogen-activated protein kinase p38 monocyte mutant neuroinflammation neuronal survival neuroprotection neurotoxicity novel public health relevance research study response tool

项目摘要

DESCRIPTION (provided by applicant): 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-12. IL-12, 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. PUBLIC HEALTH RELEVANCE: To date, almost 60 million people have been infected worldwide with the human immunodeficiency virus -1. HIV-associated neurocognitive disorder (HAND) that consists of HIV-1-associated dementia (HAD) along with other neurocognitive impairments, is an important neurological complication of HIV-1 infection. An estimated 10-15% of HIV-seropositive (HIV+) patients progress to HAD in developed worlds such as the United States, despite highly active antiretroviral therapy. Glial inflammation is an important mechanism involved in this disease and the data from this proposal will provide a better understanding of the specific mechanistic contributions of activated glia to HIV-1-dementia and have broader implications for neuroprotection.

描述（由申请人提供）：目前，全世界有近 3500 万人感染 HIV-1。 HIV-1相关性痴呆(HAD)与轻度神经认知障碍和无症状神经认知障碍一起构成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相关的潜在机制及其在神经艾滋病中的贡献进行新的研究。初步实验使用了原代人胶质细胞，CXCL8 是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。重要的是，CXCL8 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。这一观察结果的生物学相关性得到了进一步证实，因为与年龄匹配的对照相比，HIV-1 感染的脑组织表现出更高的 CXCL8 水平。我们认为CXCL8在HIV-1 CNS感染的细胞间相互作用中发挥关键的调节作用。小胶质细胞感染和激活导致 IL-12 上调。 IL-12 是星形胶质细胞的一种典型炎症刺激物，可增强中枢神经系统中星形胶质细胞的 CXCL8 产生。 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。总而言之，这些事件最终可能导致 CXCL8 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 中激活的星形胶质细胞中的 CXCL8 是如何受到调节的以及涉及哪些机制？（目标 1）胶质细胞 CXCL8 如何调节小胶质细胞的招募、激活和感染？（目标2）CXCL8如何在HAD过程中调节神经元的存活和/或功能？（目标 3）在目标 1 中，将利用人脑组织标本和原代人神经细胞来描绘 CXCL8 谱并鉴定 HAD 中 CXCL8 的细胞来源。原代人类神经细胞将受到 HAD 特异性刺激，并评估 CXCL8 调节。将在星形胶质细胞中研究参与 IL-8 调节的细胞内信号通路，特别是 NF-:B、p38MAPK 和/或 SHP2。目标 2 将评估激活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在调节小胶质细胞激活、招募和 HIV-1 感染中的作用。CXCL8 神经保护的机制以及随后特别通过 Akt/PKB、ERK1 的信号转导/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目标 3 中的原代人类神经元进行研究。总而言之，本申请中提出的研究将提供有关 CXCL8 介导的神经胶质串扰和神经发病机制的新数据，并对神经胶质炎症反应的调节产生新的见解，具有基础和临床意义。公共卫生相关性：迄今为止，全世界已有近 6000 万人感染人类免疫缺陷病毒 -1。 HIV 相关神经认知障碍 (HAND) 由 HIV-1 相关痴呆 (HAD) 和其他神经认知障碍组成，是 HIV-1 感染的重要神经并发症。据估计，在美国等发达国家，尽管进行了高效的抗逆转录病毒治疗，仍有 10-15% 的 HIV 血清阳性 (HIV+) 患者进展为 HAD。神经胶质炎症是这种疾病的重要机制，该提案的数据将有助于更好地理解激活的神经胶质细胞对 HIV-1 痴呆的具体机制贡献，并对神经保护产生更广泛的影响。