TRAIL and glutaminase: neurotoxic link in HIV-1 Dementia

TRAIL 和谷氨酰胺酶：HIV-1 痴呆中的神经毒性联系

基本信息

批准号：
7407429
负责人：
Jialin Charles Zheng
金额：
$ 29.01万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-06-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7407429
关键词：
AIDS Dementia Complex AIDS/HIV problem Adenoviruses Affect Animal Model Antibodies Apoptosis Apoptotic Automobile Driving Autopsy BIRC1 gene BIRC4 gene Binding Biological Biological Assay Biological Testing Brain Cell Death Cells Cessation of life Clinical Coculture Techniques Consequences of HIV Data Dementia Disease Down-Regulation Encephalitis Environment Event Gene Expression Gene Proteins Genes Genetic Glutamates Glutaminase Grant HIV Envelope Protein gp120 HIV-1 Human Immune Immunity In Vitro Infection Inflammation Inflammatory Inflammatory Response Investigation Laboratories Ligands Link Location Macrophage Activation Measurement Measures Mediating Mediator of activation protein Methods Microglia Mitochondria Molecular Mononuclear Nerve Degeneration Neurodegenerative Disorders Neuronal Injury Neurons Neuropathogenesis Neurovirology Nuclear Outcome Pathogenesis Pathway interactions Patients Peripheral Nervous System Diseases Phagocytes Pharmacotherapy Physiology Polymerase Chain Reaction Prevention Process Production Protein Family Protein Isoforms Proteins RNA Interference Receptor Signaling Recombinants Regulation Relative (related person)Research Resources Role Secondary to Signal Pathway Signal Transduction Signaling Molecule Small Interfering RNA System TNF gene Technology Testing Time Transfection Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha Tumor Necrosis Factors Tumor necrosis factor receptor 11b Up-Regulation Viral Proteins Virus Diseases Western Blotting Work X-linked IAP XAF1 gene base brain tissue caspase-8 cell injury cytokine expectation extracellular human HSXIAPAF1 protein human TNF protein in vivo inhibitor-of-apoptosis protein inhibitor/antagonist macrophage member monocyte nervous system disorder neuron apoptosis neuron loss neuronal apoptosis inhibitory protein neuronal tumor neurotoxic neurotoxicity novel therapeutics protein expression receptor receptor expression research study response therapeutic target tissue culture

项目摘要

DESCRIPTION (provided by applicant): Brain inflammation underlies the neuropathogenesis of HIV-1 infection. What triggers neuronal death and the inflammatory mechanism driving neurological disease affects multiple neurodegenerative disorders including HIV-1-associated dementia (HAD). One important and newly discovered inflammatory mediator implicated in the pathogenesis of HAD is TRAIL. TRAIL, a member of the TNF superfamily, mediates immunoregulatory and inflammatory responses through its interaction with TRAIL receptor one (R1) and two (R2), decoy receptors (R3 and R4), and a soluble receptor, osteoprotegerin (OPG). Recently, we demonstrated that TRAIL is upregulated on HIV-infected, immune-activated macrophages. Importantly, TRAIL induces neuronal cell death by binding to neuronal death receptors. Of further importance to HAD are the described links between glutamate and TRAIL. HIV-1 infection of macrophage leads to the upregulation of glutaminase C (the GAC isoform of the glutaminase gene) and consequently increased glutamate production. Recombinant TRAIL enhances HIV-1 infected macrophage death leading to the significant increase of glutamate production that affects macrophage mediated neuronal injury. Based on these preliminary results, this competitive renewal proposal will examine the hypothesis that an important inflammatory event in HAD is the upregulation of TRAIL expression. We argue that this is a significant pathogenic event that triggers macrophage-neuron and macrophage-macrophage interactions engaging death receptors and affecting signaling events eventually leading to generalized cell death. Moreover, we hypothesize that a specific consequence of TRAIL mediated MP death is glutaminase release, increasing drain glutamate levels and leading to secondary neuronal death. This project will develop assays that mimic brain macrophage activation, neuronal injury and apoptotic signaling that occur in HAD. The elucidation of the mechanisms by which TRAIL-TRAIL receptors and glutaminase interact during MP mediated neuronal injury may open up new therapeutic ideas for disease treatment or prevention.

描述（由申请人提供）：脑部炎症是HIV-1感染的神经病的基础。触发神经元死亡和驱动神经疾病的炎症机制的原因会影响多种神经退行性疾病，包括HIV-1相关痴呆症（HAT）。涉及HAD发病机理的一种重要且新发现的炎症介质是Trail。 TRAIL是TNF超家族的成员，通过与Trail受体ONE（R1）和两个（R2），诱饵受体（R3和R4）以及可溶性受体，骨蛋白酶蛋白酶（OPG）的相互作用，介导免疫调节和炎症反应。最近，我们证明了TRAIL在感染HIV的免疫激活巨噬细胞上被上调。重要的是，TRAIL通过与神经元死亡受体结合而诱导神经元细胞死亡。更重要的是谷氨酸和步道之间所描述的联系。巨噬细胞的HIV-1感染导致谷氨酰胺酶C（谷氨酰胺酶基因的GAC同工型）的上调，从而增加了谷氨酸的产生。重组小径增强了HIV-1感染的巨噬细胞死亡，导致谷氨酸产生的显着增加，从而影响巨噬细胞介导的神经元损伤。基于这些初步结果，该竞争性更新建议将研究以下假设：其中重要的炎症事件是跟踪表达的上调。我们认为，这是一个重要的致病事件，可触发巨噬细胞神经元和巨噬细胞巨噬细胞相互作用吸引死亡受体，并影响信号事件，最终导致广义细胞死亡。此外，我们假设TRAIL介导的MP死亡的特定后果是谷氨酰胺酶释放，增加了排水谷氨酸水平并导致继发性神经元死亡。该项目将开发出模仿大脑巨噬细胞激活，神经元损伤和凋亡信号的测定法。在MP介导的神经元损伤过程中，迹象机制阐明了Trail-Trail受体和谷氨酰胺酶相互作用的机制可能为疾病治疗或预防提供新的治疗思想。