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

慢性疼痛共病情绪障碍的替代多聚腺苷酸化（APA）机制

• 批准号: 10572902
• 负责人: Lingyong Li
• 金额: $ 42.73万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10572902
• 关键词: 3' Untranslated Regions; Address; Affective; Anterior; Anxiety; Behavioral Symptoms; Brain; Brain region; Chronic inflammatory pain; Clinical; Coupled; Custom; Data; Event; Gene Expression; Generations; Genes; Genetic Transcription; Huntington Disease; Knowledge; Laboratories; Length; Lesion; Maps; Mediating; Mental Depression; Messenger RNA; MicroRNAs; Modeling; Molecular; Mood Disorders; Moods; Mus; Neurons; Oculopharyngeal Muscular Dystrophy; Output; Parkinson Disease; Patients; Poly A; Polyadenylation; Process; Protein Isoforms; Publishing; RNA-Binding Proteins; Regulation; Research; Rodent Model; Role; Site; Stress; Symptoms; Testing; Therapeutic; Transcript; Translations; Untranslated Regions; Work; anxiety symptoms; anxiety-like behavior; associated symptom; chronic neuropathic pain; chronic pain; chronic pain management; chronic pain patient; cingulate cortex; comorbidity; computational pipelines; depressive symptoms; design; genome-wide; hippocampal pyramidal neuron; insight; mRNA Stability; multidisciplinary; nerve injury; optogenetics; pain model; pain processing; painful neuropathy; prevent; sequencing platform; spared nerve

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.

项目摘要/摘要 这个项目的主要目标是确定替代的多聚腺苷酸化(APA)机制 慢性疼痛潜在的抑郁和焦虑并存症状。情绪障碍，如抑郁和 焦虑常见于慢性疼痛患者。这些“共病”的情绪障碍在临床上是 很难治疗，而且它们会显著加剧患者的痛苦。尽管有类似的行为症状，但 慢性疼痛引起的情绪障碍和压力引起的情绪障碍的潜在机制是不同的。 已知前扣带回皮质(ACC)是此类并存疾病的关键中枢之一。 与慢性疼痛相关的抑郁/焦虑症状，以及慢性疼痛诱导显著的基因表达 ACC的变化，代表了共病情绪障碍的基本机制。尽管如此 令人信服的观察，在ACC内驱动共病情绪的潜在基因表达变化 慢性疼痛的障碍仍然不清楚，代表着一种关键的知识差距。交替多聚腺苷 (APA)是改变大脑内基因输出的主要机制。APA产生信使核糖核酸的过程 具有不同长度的非翻译区(3‘UTR)的异构体，它在转录后调节mRNA的稳定性， 本地化和翻译率。大脑中的裂解和多聚腺苷酸化机制的异常调节 与帕金森氏症、眼咽肌营养不良症和亨廷顿病有关。 在这个合作和多学科的项目中，具有慢性疼痛专业知识的神经科学家李凌勇博士 和共病的情绪障碍，和埃里克·瓦格纳博士，替代多聚腺苷领域的专家，将合作 并测试Nudt21调节的ACC神经元APA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)探讨ACC Nudt21的作用 慢性神经病理性疼痛诱导的抑郁/焦虑症状的表达；(2)确定特定基因对象 Nudt21调节的ACC神经元内的APA对慢性疼痛诱导的情绪障碍非常重要。因为 调控失调的APA介导的基因表达变化在共病情绪障碍中的关键作用尚未得到证实 之前已经认识到，我们使用APA机制来回答这些问题可能会改变我们对 APA失调如何定义和促进慢性疼痛的共病情绪障碍。我们期待着新的 这一提议的发现将提供一个新的图景来理解潜在的分子机制。 慢性疼痛的共病情绪障碍为治疗慢性疼痛提供了全新的可能性 慢性疼痛管理。