Microglia adenine nucleotides and hypoxia

小胶质细胞腺嘌呤核苷酸和缺氧

• 批准号: 7433732
• 负责人: JYOTI J WATTERS
• 金额: $ 25.25万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7433732
• 关键词: ATP Receptors; Address; Adenine Nucleotides; Brain; Brain Injuries; Breathing; CREB1 gene; Disease; Heart; Hypoxia; Hypoxic Brain Damage; Inflammation; Inflammatory; Lipopolysaccharides; Lung diseases; MAP Kinase Signaling Pathways; MAPK14 gene; Mediating; Mediator of activation protein; Microglia; Mitogen-Activated Protein Kinases; Modeling; Molecular; Neurons; Pathway interactions; Phosphorylation; Production; Proteins; Purinoceptor; Reactive Oxygen Species; Receptor Activation; Receptor Inhibition; Receptor Signaling; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Stimulus; Stroke; Testing; Therapeutic; Work; cytokine; extracellular; human MAPK14 protein; interest; mitogen-activated protein kinase p38; neuroprotection; neurotoxic; prevent; receptor; response; transcription factor

DESCRIPTION (provided by applicant): Microglial cell hyperactivation following hypoxic brain injury, and their release of neurotoxic inflammatory mediators into the CNS contributes to inflammation and damage. Hence, modulation of microglial cell activity is of great interest to decrease or prevent neuronal damage following brain injury from stroke, heart or lung disease and breathing disorders. Extracellular adenine nucleotides are important modulators of microglial cell inflammatory capacity, and they are abundant following brain injury. Although much work has been done elucidating the mechanisms involved in ATP stimulation of microglial inflammatory cytokines, little is known about their complementary inhibitory effects on microglial inflammatory mediator production. The fundamental hypothesis guiding this proposal is that extracellular adenine nucleotides exert neuroprotective effects in the brain by interacting with purinergic receptor signal transduction pathways to decrease microglial cell activation. We will investigate the molecular mechanisms underlying adenine nucleotide mediated neuroprotection in microglial cell cultures using two models of microglial activation: bacterial lipopolysaccharide (LPS) or hypoxia. Four specific aims are proposed to test mechanisms by which purinergic receptors influence microglial production of neurotoxic/inflammatory mediators, focusing on purinergic receptor MAP kinase pathways and transcription factor activation profiles. Purinergic receptor activation decreases microglial cell activity in response to several microglial activators, suggesting that purinergic receptors interact with signaling pathways common to different stimuli. However, purinergic receptor activation can cause deleterious effects in some situations, implying that therapeutic modulation of certain purinergic receptors may result in different effects depending upon the pre-existing microglial activation status. Results of this work will aid in the identification of new pharmacologic targets that may be exploited therapeutically to control microglial activation in response to several stimuli including hypoxia.

描述（由申请方提供）：缺氧性脑损伤后小胶质细胞过度活化，其释放神经毒性炎症介质进入CNS，导致炎症和损伤。因此，小胶质细胞活性的调节对于减少或预防中风、心脏或肺部疾病和呼吸障碍引起的脑损伤后的神经元损伤具有极大的意义。细胞外腺嘌呤核苷酸是小胶质细胞炎症能力的重要调节剂，并且在脑损伤后含量丰富。虽然已经做了很多工作，阐明参与ATP刺激小胶质细胞炎性细胞因子的机制，很少有人知道他们的互补抑制作用小胶质细胞炎症介质的生产。指导这一提议的基本假设是细胞外腺嘌呤核苷酸通过与嘌呤能受体信号转导通路相互作用以减少小胶质细胞活化而在脑中发挥神经保护作用。我们将研究腺嘌呤核苷酸介导的神经保护作用的分子机制，在小胶质细胞培养使用两种模型的小胶质细胞活化：细菌脂多糖（LPS）或缺氧。提出了四个具体的目标来测试嘌呤能受体影响小胶质细胞产生神经毒性/炎症介质的机制，重点是嘌呤能受体MAP激酶途径和转录因子激活谱。嘌呤能受体激活降低小胶质细胞的活性，在几个小胶质细胞激活剂，表明嘌呤能受体相互作用的信号通路共同不同的刺激。然而，在某些情况下，嘌呤能受体活化可引起有害作用，这意味着某些嘌呤能受体的治疗性调节可根据预先存在的小胶质细胞活化状态产生不同的作用。这项工作的结果将有助于识别新的药理学靶点，这些靶点可用于治疗控制小胶质细胞对包括缺氧在内的几种刺激的激活。