Validating ASCT2 for the Treatment of Chronic Postsurgical Pain

验证 ASCT2 治疗慢性术后疼痛的效果

• 批准号: 9974791
• 负责人: Ohannes Kevork Melemedjian
• 金额: $ 154.5万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9974791
• 关键词: Acute Pain; Adopted; Affect; Afferent Neurons; Attenuated; Biochemical; Biochemical Process; Biological Assay; Catabolism; Cell physiology; Cells; Chronic; Citric Acid Cycle; Clinical; Data; Dependence; Development; Event; Genes; Genetic Polymorphism; Glutamine; Goals; Health; Incidence; Injections; Injury; Knowledge; Lead; Link; Measures; Mediating; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Molecular; Molecular Target; Mus; Neurons; Nutrient; Operative Surgical Procedures; Opioid; Oxides; Pain; Patients; Persistent pain; Postoperative Pain; Postoperative Period; Process; Public Health; Pyruvate; RNA; Recovery; Research; Resolution; Risk; Role; Safety; Site; Supplementation; Surgical incisions; Therapeutic; Translations; Trauma; Validation; Viral; base; chronic pain; chronic pain patient; experience; flexibility; fluorescence imaging; healing; imaging modality; immunogenicity; in vivo; innovation; knock-down; molecular targeted therapies; novel; novel therapeutics; overexpression; oxidation; prevent; sensor; side effect; therapy development; treatment strategy

Pain associated with surgery is experienced by millions of patients every year. Post-surgical pain usually resolves as the surgical site heals. However, up to half of the patients develop chronic pain after surgery. Crucially, little is known about the mechanisms that aid in the resolution of postoperative pain. Moreover, opioids remain the mainstay treatment for post- surgical pain which are fraught with serious side-effects and crucially - abuse liabilities. The goal of our research is to validate an endogenous mechanism that leads to the resolution of post- surgical pain. Metabolism is inextricably linked to every aspect of cellular function. However, the specific effects surgery has on the metabolism of sensory neurons and how these changes influence the resolution of post-surgical pain are not known. Hence, we determined that surgical trauma suppresses pyruvate oxidation while increase glutamine catabolism was associated with the resolution of post-surgical pain. The selective increase of glutamine oxidation was in part mediated by the glutamine transporter ASCT2 which replenished the Krebs cycle metabolic intermediates that have been depleted due to reduced pyruvate oxidation. This process is known as anaplerosis. Moreover, disruption of ASCT2 expression prevented the resolution of postoperative pain. Hence, we aim to validate that ASCT2 is critical for the resolution of post- surgical pain and can be manipulated for the resolution of postoperative pain. Using molecular, biochemical, metabolic assays and innovative multiband fluorescence imaging method of intact DRGs, we aim to achieve our objective. Moreover, we propose to validate an innovative RNA- based strategy that enhances ASCT2 expression. Validation of endogenous targets that resolve postoperative pain can have broad impact in advancing our knowledge of the transition of acute pain to chronic and lead to urgently needed public health advancements.

每年有数百万患者经历与手术相关的疼痛。术后 疼痛通常随着手术部位的愈合而消退。然而，多达一半的患者发展为 术后慢性疼痛至关重要的是，人们对这种机制知之甚少， 缓解术后疼痛。此外，阿片类药物仍然是治疗后， 手术疼痛，这是充满了严重的副作用和严重滥用的责任。目标 我们的研究是验证一种内源性机制，导致解决后- 手术疼痛。新陈代谢与细胞功能的各个方面密不可分。然而，在这方面， 手术对感觉神经元代谢的具体影响以及这些变化 影响术后疼痛的解决尚不清楚。因此，我们确定， 创伤抑制丙酮酸氧化，而谷氨酰胺催化剂增加与 术后疼痛的缓解谷氨酰胺氧化的选择性增加部分是由于 由谷氨酰胺转运蛋白ASCT 2介导，其补充克雷布斯循环代谢 由于丙酮酸氧化减少，中间体已经耗尽。这个过程是 称为回补。此外，ASCT 2表达的破坏阻止了 术后疼痛因此，我们的目标是验证ASCT 2对于解决后 手术疼痛，并可用于解决术后疼痛。使用分子， 生物化学、代谢分析和创新的多波段荧光成像方法， DRGs，我们的目标是实现我们的目标。此外，我们建议验证一种创新的RNA- 基于增强ASCT 2表达的策略。验证可解决的内源性靶标 术后疼痛对我们了解急性胰腺炎的转变有着广泛的影响， 慢性疼痛，并导致迫切需要的公共卫生进步。