GLIAL GLUTAMATE TRANSPORTER EAAT2 AND VISCERAL PAIN

胶质谷氨酸转运蛋白 EAAT2 与内脏疼痛

基本信息

批准号：
7213597
负责人：
ROBERT L STEPHENS
金额：
$ 15万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7213597
关键词：
Abdominal Pain Affect Alternative Splicing Analgesics Animals Biological Assay Brain Cell Nucleus Chronic Defecation Diagnosis Digestive System Disorders Disease Doctor of Philosophy Dorsal Evaluation Excitatory Amino Acid Transporter 2 Functional disorder Gastroenterologist Gene Transfer Glutamate Transporter Glutamates Goals Human Hyperalgesia Hypersensitivity Intestines Irritable Bowel Syndrome Laboratories Laboratory Study Magnesium Sulfate Mediating Modeling Mus N-Methyl-D-Aspartate Receptors Neonatal Nociception Pain Patients Pharmacogenetics Population Principal Investigator Protein Overexpression Rattus Receptor Activation Recurrence Role Site Spinal Spinal Cord Substance administration Therapeutic Transgenic Animals Transgenic Mice Transgenic Organisms Validation Variant Visceral Visceral pain Work central sensitization colorectal distension dorsal horn extracellular gastrointestinal function gene therapy insight intraperitoneal neurotransmission nociceptive response novel protective effect research study response transmission process uptake

项目摘要

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.

描述（由申请人提供）：肠易激综合征（IBS）是胃肠病学家的主要消化诊断，影响了15-20％的美国人群。 IBS患者的主要抱怨是腹痛复发，排便受干扰。 NMDA受体激活介导的中心敏化与这些疾病有关。在研究谷氨酸转运蛋白（LIN C.G-CO-主要研究者）与研究疼痛和胃肠道功能（Stephens，R.L。主要研究者）研究谷氨酸转运蛋白（Lin C.G-CO主要研究者）之间的合作项目中，已经发起了与谷氨酸转运蛋白功能相关的可塑性在介导的内脏疼痛中的作用的研究。谷氨酸转运蛋白功能的功能障碍是慢性和持续性疼痛的病理生理学中的新主题。过表达人EAAT2谷氨酸转运蛋白的转基因小鼠在内脏疼痛的鼠扭动模型中受到了显着保护的，负责控制细胞外谷氨酸的谷氨酸转运蛋白。提出了实验来确认和扩展这些发现，以深入了解介导内脏痛觉过敏的机制。提出了两个假设。 1）评估在EAAT2过表达转基因动物中的内脏伤害感受的其他鼠模型，以及2）在已知的内脏伤害性神经传递的已知地点的增强的谷氨酸摄取与转基因动物产生的保护作用相关联。验证EAAT2过表达的转基因方法对慢性内脏疼痛治疗的潜在药物遗传学途径具有明显的影响。随后的亚临床方法将是在新生儿有害暴露大鼠模型中产生EAAT2的靶向基因转移，从而产生内脏超敏反应。