GLIAL GLUTAMATE TRANSPORTER EAAT2 AND VISCERAL PAIN

描述（由申请人提供）：肠易激综合征（IBS）是胃肠病学家诊断的主要消化系统疾病，影响了15-20%的美国人口。肠易激综合征患者的主要主诉是反复腹痛伴排便紊乱。NMDA受体激活介导的中枢致敏与这些疾病有关。在这个研究谷氨酸转运蛋白的实验室（Lin c.g -联席首席研究员）和一个研究疼痛和胃肠功能的实验室（Stephens, r.l. -首席研究员）的合作项目中，已经开始研究与谷氨酸转运蛋白功能相关的可塑性在介导内脏疼痛中的作用。谷氨酸转运体功能障碍是慢性和持续性疼痛病理生理学中的一个新兴主题。过表达人EAAT2谷氨酸转运蛋白的转基因小鼠在小鼠内脏疼痛扭体模型中受到明显保护，EAAT2是控制细胞外谷氨酸的数量优势转运蛋白。实验被提出来证实和扩展这些发现，以深入了解介导内脏痛觉过敏的机制。提出了两个假设；1)评估其他小鼠内脏伤害感受模型对过表达EAAT2的转基因动物的保护作用；2)在内脏伤害感受神经传递的已知位点增加谷氨酸摄取与转基因动物产生的保护作用之间的关系。EAAT2过表达的转基因方法的验证对于治疗慢性内脏疼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有害暴露产生内脏过敏的大鼠模型中产生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.