GLIAL GLUTAMATE TRANSPORTER EAAT2 AND VISCERAL PAIN

描述(由申请人提供)：肠易激综合征(IBS)是胃肠病专家的主要消化系统疾病诊断，影响美国15%-20%的人口。IBS患者的主要主诉是反复腹痛和肠道运动障碍。由NMDA受体激活介导的中枢敏化与这些疾病有关。在一个研究谷氨酸转运体的实验室(联席首席研究员林C.G)和一个研究疼痛和胃肠功能的实验室(斯蒂芬斯，R.L.-首席研究员)的合作项目中，与谷氨酸转运体功能相关的可塑性在调节内脏疼痛中的作用的研究已经启动。谷氨酸转运体功能障碍是慢性持续性疼痛的病理生理学研究热点之一。过量表达人EAAT2谷氨酸转运蛋白的转基因小鼠在内脏痛小鼠扭体模型中得到显著保护。建议进行实验以证实和扩展这些发现，以深入了解调节内脏痛觉过敏的机制。提出了两个假设：1)评估其他内脏伤害性感受的小鼠模型在EAAT2过表达转基因动物中的保护作用；2)将内脏伤害性神经传递已知部位增加的谷氨酸摄取与转基因动物产生的保护作用联系起来。EAAT2过表达转基因方法的验证对治疗慢性内脏痛的潜在药物遗传学途径具有重要意义。随后的亚临床方法将是在新生儿伤害性暴露产生内脏超敏反应的大鼠模型中产生EAAT2的靶向基因转移。

DESCRIPTION (provided by applicant): Irritable bowel syndrome (IBS) is the leading digestive disease diagnosis among gastroenterologists and affect 15-20% of the US population. The predominant complaint of IBS patients is RECURRENT ABDOMINAL PAIN with disturbed bowel movements. Central sensitization mediated by the NMDA receptor activation is implicated in these disorders. In this collaborative project between a laboratory that studies glutamate transporters (Lin C.G-Co-Principal Investigator) and one that studies pain and gastrointestinal function (Stephens, R.L.-Principal Investigator) the study of the role of plasticity related to glutamate transporter function in mediating visceral pain has been initiated. Dysfunction of glutamate transporter function is an emerging theme in the pathophysiology of chronic and persistant pain. Transgenic mice overexpressing human EAAT2 glutamate transporter, the quantitatively dominant glutamate transporter responsible for controlling extracellular glutamate, were markedly protected in the murine writhing model of visceral pain. Experiments are proposed to confirm and extend these findings to gain insight into mechanisms mediating visceral hyperalgesia. Two hypotheses are proposed; 1) to assess other murine models of visceral nociceptions for protective effect in EAAT2 overexpressing transgenic animals and 2) to correlate augmented glutamate uptake at known sites of visceral nociceptive neurotransmission with protective effects produced by transgenic animals. Validation of the transgenic approach of EAAT2 overexpression has marked implications for potential pharmacogenetic avenues of therapy of chronic visceral pain. Subsequent subclinical approaches would be to produce targeted gene transfer of EAAT2 in rat models of neonatal noxious exposure which produces visceral hypersensitivity.