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：
8109269
负责人：
Anuja Ghorpade
金额：
$ 35.64万
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/8109269
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 G Protein-Coupled Receptor Genes G-Protein-Coupled Receptors Genes Glial Fibrillary Acidic Protein HIV HIV encephalitis HIV-1 Health 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 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 neurocognitive impairment mitogen-activated protein kinase p38 monocyte mutant neuroinflammation neuronal survival neuroprotection neurotoxicity novel 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3500万人居住着HIV-1感染。 HIV-1相关痴呆症（患有）与轻度神经认知障碍和无症状的神经认知障碍包括HIV相关的神经认知障碍（HARD）。与温和形式的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。几年前，我们开始研究与神经胶质激活相关的潜在机制及其在神经辅助中的贡献。原代人神经胶质细胞用于初步实验，CXCL8是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之一。重要的是，CXCL8在暴露于HIV-1相关神经毒素的培养的人神经元中是神经保护作用。该观察结果的生物学相关性得到了进一步的证实，因为与年龄匹配的对照相比，HIV-1感染的脑组织表现出更大的CXCL8水平。我们建议CXCL8在HIV-1 CNS感染的细胞间相互作用中起关键的调节作用。小胶质细胞感染和激活导致IL-12的上调。 IL-12是一种用于星形胶质细胞的典型炎症刺激，可增强CNS中星形胶质细胞的CXCL8产生。 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。总的来说，这些事件最终可能导致CXCL8介导的直接或间接神经保护。对于这些目的，我们将解决以下特定问题：在活化的星形胶质细胞中，CXCL8如何调节HAT和哪些机制？（AIM 1）神经胶质CXCL8如何调节小胶质细胞募集，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？（AIM 3）在AIM 1中，将利用人脑组织标本和原发性人神经细胞来描述CXCL8概况，并确定CXCL8的细胞源。原发性人神经细胞将暴露于特异性刺激中，并评估CXCL8调节。涉及IL-8调控的细胞内信号传导途径，特别是NF-：B，P38MAPK和/或SHP2，将在星形胶质细胞中研究。在AIM 2中，将评估活化星形胶质细胞与小胶质细胞之间细胞间相互作用在小胶质细胞激活，募集和HIV-1感染中的作用。在AIM 3中，将使用原发性人神经元研究神经保护事件。总而言之，本应用中提出的研究将提供有关CXCL8介导的神经胶质跨对词和神经发病的新数据，并导致对具有碱性和临床意义的神经胶质炎症反应的调节的新见解。公共卫生相关性：迄今为止，近6000万人已被人类免疫缺陷病毒-1感染。 HIV相关的神经认知障碍（手）由HIV-1相关痴呆（HAT）以及其他神经认知障碍，是HIV-1感染的重要神经系统并发症。尽管高度活跃的抗逆转录病毒疗法，但估计有10-15％的HIV - 呼吸阳性（HIV+）患者在美国等发达国家的发展。神经胶质炎症是该疾病中涉及的重要机制，该提案的数据将更好地理解激活的神经胶质对HIV-1降解的特定机理贡献，并对神经保护具有更广泛的影响。