Alternative polyadenylation(APA) mechanisms of comorbid mood disorders in chronic pain

项目总结/摘要 本项目的主要目的是确定替代的多聚腺苷酸化（阿帕）机制 慢性疼痛中潜在的抑郁和焦虑共病症状。情绪障碍，如抑郁症和 在患有慢性疼痛的患者中经常观察到焦虑。这些“共病”情绪障碍在临床上是 很难治疗，而且会大大加重患者的痛苦。尽管有类似的行为症状， 慢性疼痛诱发的心境障碍与压力诱发的心境障碍的潜在机制是不同的。 已经知道前扣带皮层（ACC）是共病的一个这样的关键枢纽。 抑郁/焦虑症状与慢性疼痛相关，慢性疼痛诱导显著的基因表达 ACC的变化，代表共病情绪障碍的基本机制。尽管有这些 令人信服的观察，ACC内驱动共病情绪的潜在基因表达变化 慢性疼痛障碍仍然不清楚，代表着一个关键的知识缺口。交替多聚腺苷酸化 (APA)是改变大脑基因输出的主要机制。阿帕过程产生mRNA 具有不同非翻译区（3 'UTR）长度的同种型，其在转录后调节mRNA稳定性， 本地化和翻译率。大脑中分裂和多聚腺苷酸化机制的异常调节 与帕金森氏病、眼咽肌营养不良和亨廷顿氏病有关。 在这个合作和多学科的项目中，Lingyong Li博士，一位在慢性疼痛方面具有专长的神经科学家， 和共病情绪障碍，和埃里克瓦格纳博士，在替代多聚腺苷酸化领域的专家，将合作 并测试Nudt 21调节ACC神经元中的阿帕介导慢性疼痛的总体假设。 抑郁/焦虑的后果。本申请的具体目的是（1）探索ACC Nudt 21的作用 在慢性神经病理性疼痛诱导的抑郁/焦虑症状中的表达;（2）鉴定受试者的特定基因 Nudt 21调节的ACC神经元内的阿帕对慢性疼痛诱导的情绪障碍很重要。因为 APA介导的基因表达异常在共病情绪障碍中的关键作用尚未被证实。 我们以前认识到，我们使用阿帕机制来回答这些问题可以改变我们对 阿帕失调如何定义和促成慢性疼痛中的共病情绪障碍。我们期待新的 这一提议的发现将为理解潜在的分子机制提供一个新的视角。 慢性疼痛中的共病情绪障碍，并提供了一个全新的治疗可能性， 慢性疼痛管理

PROJECT SUMMARY/ABSTRACT The primary objective of this project is to determine the alternative polyadenylation (APA) mechanisms underlying comorbid depressive and anxiety symptoms in chronic pain. Mood disorders such as depression and anxiety are frequently observed in patients with chronic pain. These 'comorbid' mood disorders are clinically difficult to treat, and they can significantly intensify patient suffering. Despite similar behavioral symptoms, the mechanisms underlying chronic pain-induced mood disorders versus stress-induced mood disorders are distinct. It has been known that the anterior cingulate cortex (ACC) is one such critical hub for comorbid depressive/anxiety symptoms associated with chronic pain, and chronic pain induces marked gene expression changes in the ACC, representing the fundamental mechanism of comorbid mood disorders. Despite these compelling observations, the underlying gene expression changes within the ACC that drive comorbid mood disorders in chronic pain remain unclear and represent a critical knowledge gap. Alternative polyadenylation (APA) is a major mechanism that alters gene output within the brain. The process of APA generates mRNA isoforms with varying untranslated region (3'UTR) lengths, which post-transcriptionally regulate mRNA stability, localization, and translation rate. Abnormal regulation of the cleavage and polyadenylation machinery in the brain has been associated with Parkinson's disease, oculopharyngeal muscular dystrophy, and Huntington's disease. In this collaborative and multidisciplinary project, Dr. Lingyong Li, a neuroscientist with expertise in chronic pain and comorbid mood disorders, and Dr. Eric Wagner, an expert in alternative polyadenylation field, will collaborate and test the overall hypothesis that Nudt21-regulated APA in ACC neurons mediates chronic pain's depressive/anxiety consequences. The specific aims of this application are to (1) Probe the role of ACC Nudt21 expression in chronic neuropathic pain-induced depressive/anxiety symptoms; (2) Identify specific genes subject to Nudt21-regulated APA within ACC neurons important for chronic pain-induced mood disorders. Because the critical role of dysregulated APA-mediated gene expression changes in comorbid mood disorders has not been recognized previously, our use of APA machinery to answer these questions could transform our knowledge of how APA dysregulation defines and contributes to comorbid mood disorders in chronic pain. We expect that new findings from this proposal will provide a new landscape to understand the underlying molecular mechanisms of the comorbid mood disorders in chronic pain and provide an entirely new layer of therapeutic possibility for chronic pain management.