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

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

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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.

每年数百万名患者经历与手术相关的疼痛。外科手术疼痛通常会随着手术部位愈合而缓解。但是，多达一半的患者发展手术后的慢性疼痛。至关重要的是，对有助于有助于的机制知之甚少术后疼痛的分辨率。此外，阿片类药物仍然是后期的主要治疗方法手术疼痛充满了严重的副作用和至关重要的 - 滥用责任。目标我们的研究是验证一种内源性机制，导致后期解决手术疼痛。代谢与细胞功能的各个方面密不可分。然而，手术对感觉神经元的代谢以及这些如何改变影响后手术后疼痛的分辨率尚不清楚。因此，我们确定了手术创伤抑制丙酮酸氧化，而增加谷氨酰胺分解代谢与手术后疼痛的分辨率。谷氨酰胺氧化的选择性增加部分是由谷氨酰胺转运蛋白ASCT2介导的，该转运蛋白ASCT2补充了克雷布斯循环代谢由于丙酮酸氧化降低而耗尽的中间体。这个过程是被称为衰减。此外，ASCT2表达的破坏阻止了分辨率术后疼痛。因此，我们旨在验证ASCT2对于解决后的解决至关重要手术疼痛，可以操纵以解决术后疼痛。使用分子完整的生化，代谢测定和创新的多型荧光成像方法 DRG，我们旨在实现我们的目标。此外，我们建议验证创新的RNA- 基于增强ASCT2表达的策略。验证解决方案的内源性目标术后疼痛可能会在促进我们对急性过渡的了解方面产生广泛的影响长期疼痛，导致迫切需要公共卫生的进步。