Microglia, Complement, and Pain

小胶质细胞、补体和疼痛

基本信息

批准号：
7903813
负责人：
CLIFFORD J WOOLF
金额：
$ 3.44万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2009-09-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7903813
关键词：
Afferent Neurons Anaphylatoxins Apoptosis Attenuated Behavior Binding C5a anaphylatoxin receptor CCL2 gene CCL3 gene CCL8 gene CX3CL1 gene Calcium Cessation of life Complement Complement 5a Complement Activation Complement Inactivators Complement Membrane Attack Complex Excision Face Feedback Fractalkine Gene Activation Genes Hypersensitivity IL6 gene ITGAM gene Immune Immune response Immunologics In Vitro Inflammation Injury Interferon Type II Knockout Mice Lead Macrophage Inflammatory Protein-1 Membrane Microglia Modeling Molecular Profiling Monocyte Chemoattractant Protein-1 Mus Mutant Strains Mice Nature Nerve Nervous system structure Neuraxis Neuroglia Neurons Pain Pathway interactions Peripheral Peripheral nerve injury Posterior Horn Cells Predisposition Production Rattus Relative (related person)Research Personnel Rodent Role Signal Transduction Signaling Molecule Spinal Cord Stimulus Structure of trigeminal nerve spinal tract nucleus Synaptic Transmission Testing base chemokine complement C5b complement pathway cytokine dorsal horn gene induction in vivo inflammatory neuropathic pain inhibitor/antagonist injured macrophage monocyte chemoattractant protein-2 nerve injury neutralizing antibody novel null mutation pain behavior painful neuropathy programs receptor research study treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Peripheral neuropathic pain arises from diverse changes in the peripheral and central nervous systems that include a reciprocal interaction between the immune and nervous systems. We find from a microarray expression profile analysis that immunologic gene activation in microglia in the dorsal horn is a major common feature of rodent peripheral neuropathic pain models and includes most prominently a local induction of components of the complement cascade in the spinal cord. Blocking the complement cascade by depleting its components in rat spinal cord or in mutant mice reduces, moreover, pain hypersensitivity in neuropathic pain models. Based on this, we hypothesize that peripheral nerve injury results in production by injured sensory neurons of a signal that is transported to the central terminals of the afferents in the dorsal horn/spinal nucleus of the trigeminal where it acts on microglia to induce complement genes. Activation of the classical complement cascade pathway locally in the superficial dorsal horn results in production of C5a anaphylatoxin and assembly of the membrane attack complex (MAC). C5a, we hypothesize, acts via the C5a receptor to alter microglial and neuronal function, while MAC, we propose, is specifically assembled on those neurons that do not express CD59, an endogenous inhibitor of MAC assembly, and by increasing calcium influx in the neurons, increases their excitability and vulnerability to apoptosis. To test this hypothesis we propose to determine: 1) Which peripheral stimuli; activity, inflammation or axonal damage, induce complement genes in microglia in the dorsal horn 2) Which cytokines and chemokines induce complement genes in microglia, 3) The role of the complement cascade in producing neuropathic pain and specifically whether C5a or assembly of the MAC is the prime effector of the pain, and 4) If complement activation alters excitability in dorsal horn neurons sufficiently to produce excitotoxic apoptosis. We will use this information to devise and test novel treatment strategies for somatic and facial neuropathic pain based either on blocking complement gene induction in microglia or complement cascade activation in the nervous system.

描述（由申请人提供）：周围神经性疼痛来自周围和中枢神经系统的各种变化，其中包括免疫系统和神经系统之间的相互相互作用。我们从微阵列表达谱分析中发现，背喇叭中的小胶质细胞中的免疫学基因激活是啮齿动物周围神经性疼痛模型的主要共同特征，其中包括最突出的脊髓中补体级联成分的局部诱导。通过在大鼠脊髓或突变小鼠中耗尽其成分来阻止补体级联反应，此外，神经性疼痛模型中的疼痛超敏反应。基于这一点，我们假设外周神经损伤导致信号的受伤的感觉神经元在三叉神经的背角/脊柱核中传播到传入的中央末端，该信号在小胶质细胞上作用于小胶质细胞诱导补体基因。在浅表背角中本地的经典补体级联途径的激活导致C5a过敏毒素的产生和膜攻击复合物（MAC）的组装。我们假设C5A通过C5A受体起作用以改变小胶质细胞和神经元功能，而MAC建议在那些表达CD59的神经元中专门组装了MAC组装的内源性抑制剂，Mac组装的内源性抑制剂（通过神经元的钙流入量）增加了兴奋性和易受素性的兴奋性。为了检验这一假设，我们建议确定：1）哪个周围刺激；活性，炎症或轴突损伤，在背角中诱导小胶质细胞中的补体基因2）细胞因子和趋化因子在小胶质细胞中诱导补体基因，3）补体级联反应在产生神经病变疼痛的作用在产生神经性疼痛中，是否在Mac的疼痛和4的痛苦效应中，是否是产生痛苦的excemention和4）。产生兴奋性毒性凋亡。我们将使用这些信息来设计和测试针对体细胞和面部神经性疼痛的新型治疗策略，以阻止小胶质细胞中补体基因诱导或补体神经系统中的级联激活。