Validating ASCT2 for the Treatment of Chronic Postsurgical Pain

验证 ASCT2 治疗慢性术后疼痛的效果

基本信息

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
项目类别：
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

项目摘要

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。术后疼痛通常会随着手术部位的愈合而消失。然而，多达一半的患者会出现手术后慢性疼痛。至关重要的是，人们对有助于这一过程的机制知之甚少。术后疼痛的解决。此外，阿片类药物仍然是术后的主要治疗方法。手术疼痛充满了严重的副作用，最重要的是 - 滥用倾向。目标我们研究的目的是验证一种内源性机制，该机制可以解决后问题手术疼痛。新陈代谢与细胞功能的各个方面有着千丝万缕的联系。然而，手术对感觉神经元代谢的具体影响以及这些变化是如何发生的对术后疼痛缓解的影响尚不清楚。因此，我们决定手术创伤抑制丙酮酸氧化，同时增加谷氨酰胺分解代谢与手术后疼痛的解决。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 ASCT2 介导，补充克雷布斯循环代谢由于丙酮酸氧化减少而被耗尽的中间体。这个过程是称为回补。此外，ASCT2表达的破坏阻止了术后疼痛。因此，我们的目标是验证 ASCT2 对于解决术后问题至关重要手术疼痛，可以通过操纵来解决术后疼痛。利用分子，完整的生化、代谢测定和创新的多波段荧光成像方法 DRG，我们旨在实现我们的目标。此外，我们建议验证一种创新的 RNA- 基于增强 ASCT2 表达的策略。验证解决的内源性目标术后疼痛可以对提高我们对急性疼痛转变的认识产生广泛的影响。疼痛转为慢性并导致迫切需要的公共卫生进步。