Project 1: Cao

项目一：曹

• 批准号: 8883622
• 负责人: Ling Cao
• 金额: $ 20.17万
• 依托单位: UNIVERSITY OF NEW ENGLAND
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8883622
• 关键词: Affect; Afferent Neurons; Behavioral; Biological Assay; CCL17 gene; CCL2 gene; CCL22 gene; CCL3 gene; CXCL1 gene; CXCL10 gene; Calcitonin Gene-Related Peptide; Calcitonin-Gene Related Peptide Receptor; Caliber; Capsaicin; Coculture Techniques; Data; Development; Dose; Enzyme-Linked Immunosorbent Assay; Event; Functional disorder; Goals; Harvest; Hypersensitivity; In Vitro; Injury; Instruction; Knock-out; Knockout Mice; Knowledge; Laboratories; Lumbar spinal cord structure; Maintenance; Measures; Mechanics; Mediating; Mediator of activation protein; Microglia; Migraine; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Nerve; Nervous system structure; Neuraxis; Neuroglia; Neurons; Neurotransmitters; Nitric Oxide; Nociceptors; Pain; Pathway interactions; Peptides; Peripheral Nerves; Peripheral nerve injury; Persistent pain; Phase; Play; Primary Lesion; Production; Reporting; Rodent; Role; Sensory; Signal Pathway; Signal Transduction; Signaling Molecule; Small Inducible Cytokine A3; Spinal; Spinal Cord; Spinal Ganglia; Spinal cord injury; Spinal nerve structure; Structure of trigeminal ganglion; Surface; TNFRSF5 gene; Tactile; Testing; Tumor Necrosis Factor Receptor; Up-Regulation; Western Blotting; Wild Type Mouse; base; chemokine; chronic pain; design; drug development; effective therapy; human NOS2A protein; in vivo; nerve injury; neutralizing antibody; novel; pain behavior; painful neuropathy; preclinical study; receptor; relating to nervous system; response

Decades of studies have provided ample evidence that glial neuroimmune activation contributes in the development of neuropathic pain. However, knowledge regarding the role of neural-glial interactions in the pathophysiology of neuropathic pain is currently lacking. In preclinical studies, calcitonin gene related peptide (CGRP), a peptide neurotransmitter, has been shown to be involved in peripheral nerve injuryinduced tactile hypersensitivity, a behavioral sign of neuropathic pain. Previously, we have also demonstrated a critical role of central nervous system (CNS) microglial CD40 in the maintenance of mechanical hypersensitivity post-peripheral nerve injury. In the current study, the possible interactions between microglial CD40 signaling and primary afferent neuron-released CGRP in regards to they affect glial cells in the spinal cord will be investigated. We hypothesize that following peripheral nerve injury, spinal cord CD40 mediates the release of CGRP from primary afferent nociceptors and this CGRP release promotes persistent pain behavior, particularly during the maintenance phase, through the induction of proinflammatory chemokine production by glia. This central hypothesis will be tested via both in vivo and in vitro studies. An established rodent neuropathic pain model, spinal nerve L5 transection (L5Tx), will be used for the in vivo studies. Dorsal root ganglia (DRG) neuron-microglia co-cultures and mixed glial cultures will be generated for the in vitro studies. The central hypothesis will be tested through 4 specific aims: 1) Examine lumbar spinal cord chemokine production following L5Tx in CD40 KO mice vs. WT mice and the role of selected chemokines in the development of behavioral hypersensitivity; 2) Determine whether CGRP is involved in L5Tx-induced chemokine production and behavioral hypersensitivity; 3) Evaluate the role of microglial CD40 in CGRP release by primary afferent neurons; and 4) Assess glial production of selected proinflammatory chemokines and upstream signaling pathways (mainly mitogen-activated protein kinase pathways) following CGRP stimulation in mixed glial cultures. The long-term goal of our study is to further understand the pathophysiology of nerve injury-induced neuropathic pain in order to uncover novel targets for new drug development leading to more efficacious treatments of neuropathic pain.

几十年的研究已经提供了充分的证据，证明神经胶质神经免疫激活有助于