ROLE OF LIF AND NGF IN INFLAMMATION AND CHRONIC PAIN

LIF 和 NGF 在炎症和慢性疼痛中的作用

• 批准号: 6642946
• 负责人: CLAIRE E HULSEBOSCH
• 金额: $ 26.22万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6642946
• 关键词: calcitonin gene related peptide; chronic pain; enzyme linked immunosorbent assay; galanin; gene induction /repression; inflammation; laboratory rat; leukemia inhibitory factor; nerve growth factors; neurogenetics; radioimmunoassay; spinal cord injury; substance P

This project addresses the regulation of neuropeptide expression in chronic pain that appears following spinal cord injury. Such pain is often a severe affliction for the victim. A model established in our laboratories to investigate the pain that follows spinal cord injury will be utilized. In this model, pain-like behaviors that appear following hemisection of the rt spinal cord are assessed. The model reproduces the salient features of post spinal cord injury in humans. Our central hypothesis is that expression of the cytokine leukemia inhibitor factor (LIF) counteracts the development of chronic pain following spinal cord injury by increasing the expression of the neuropeptide galanin and decreasing the expression of the peptides nerve growth factor (NGF), substance and calcitonin gene related peptide. This hypothesis includes a sub-hypothesis that LIF acts on the synthesis of the latter peptides by reducing the biosynthesis of NGF. Existing evidence suggests that increased LIF reduces manifestations of pain in peripheral neuropathy and inflammation models by altering the production of neuropeptide inter cellular messengers. However, since this is unaddressed for the pain that develops following spinal cord injury, the biosynthesis of all of the above peptides and their effects on pain-like behaviors following spinal cord injury will be characterized. Time courses of effects of injury on peptide biosynthesis will be determined by analyzing peptides in tissue from the area of injury by ELISA or RIA assays and by immunocytochemistry. Roles of these peptides in pain expression will be tested by blocking their actions during times of increased expression or adding them when their expression is decreased, together with measuring pain-like behaviors in the experimental animals. The actions of LIF or NGF will be manipulated so as to increase peptide synthesis and then the action of that peptide will be blocked to establish whether modulation of peptide biosynthesis by LIF and NGF influences pain-like behaviors. Effects of LIF of inflammation and associated pain will also be characterized. Insights from this work will aid in developing treatments for pain that appears following spinal cord injury, currently a clinically intractable problem.

该项目解决了脊髓损伤后出现的慢性疼痛中神经肽表达的调节。这种痛苦通常是受害者的严重痛苦。将在我们的实验室中建立的一个模型，以研究脊髓损伤后的疼痛。在此模型中，评估了RT脊髓一半后出现的疼痛样行为。该模型重现了人类后脊髓损伤的显着特征。我们的中心假设是，通过增加神经肽甘氨酸的表达并降低肽神经生长因子（NGF），物质和钙依蛋白基因相关肽的表达，脊髓损伤后脊髓损伤后的慢性疼痛表达（LIF）抵消了慢性疼痛的发展。该假设包括一个亚通常，即LIF通过减少NGF的生物合成而作用于后一种肽的合成。现有证据表明，增加的LIF通过改变神经肽间的细胞间信使的产生来减少周围神经病和炎症模型疼痛的表现。然而，由于这对于脊髓损伤后产生的疼痛尚未解决，因此将表征上述所有肽的生物合成及其对脊髓损伤后疼痛样行为的影响。损伤对肽生物合成的影响的时间疗程将通过分析ELISA或RIA分析的损伤区域的组织中的肽和免疫细胞化学的时间来确定。 这些肽在疼痛表达中的作用将通过在表达增加或在表达降低时添加它们以及测量实验动物中的疼痛样行为时进行测试。将操纵LIF或NGF的作用，以增加肽合成，然后将阻止该肽的作用，以确定LIF和NGF对肽生物合成的调节是否会影响疼痛样行为。 LIF的炎症和相关疼痛的影响也将被表征。这项工作的见解将有助于开发脊髓损伤后出现的疼痛的治疗方法，目前在临床上棘手。