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 该项目的主要目的是确定替代聚腺苷酸化（APA）机制 慢性疼痛中的基本合并症抑郁症和焦虑症状。情绪障碍，例如抑郁症和 慢性疼痛患者经常观察到焦虑。这些“合并”情绪障碍在临床上是 很难治疗，它们可以大大加剧患者的痛苦。尽管有类似的行为症状，但 慢性疼痛引起的情绪障碍与压力引起的情绪障碍的机制是不同的。 众所周知，前扣带回皮层（ACC）是合并症的关键枢纽 与慢性疼痛相关的抑郁/焦虑症状，慢性疼痛会引起明显的基因表达 ACC的变化，代表合并情绪障碍的基本机制。尽管如此 引人入胜的观察结果，在ACC中的基因表达会变化，以驱动合并情绪 慢性疼痛的疾病尚不清楚，代表着关键的知识差距。替代聚腺苷酸化 （APA）是改变大脑中基因输出的主要机制。 APA的过程产生mRNA 具有不同翻译区（3'UTR）长度的同工型，在转录后调节mRNA稳定性， 本地化和翻译率。大脑中裂解和聚腺苷酸化机制的异常调节 与帕金森氏病，脑咽肌营养不良和亨廷顿氏病有关。 在这个合作和多学科项目中，具有慢性疼痛专业知识的神经科学家Lingyong Li博士 以及合并症情绪障碍，以及替代聚腺苷酸化领域的专家埃里克·瓦格纳（Eric Wagner）博士将合作 并测试了总体假设，即ACC神经元中NUDT21调节的APA介导了慢性疼痛 抑郁/焦虑后果。本应用的具体目的是（1）探测ACC NUDT21的作用 慢性神经性疼痛引起的抑郁/焦虑症状的表达； （2）确定特定基因受试者 对于ACC神经元内NUDT21调节的APA，对于慢性疼痛引起的情绪障碍很重要。因为 合并情绪障碍中APA介导的基因表达变化的关键作用尚未 以前认识到，我们使用APA机械回答这些问题可能会改变我们对 APA失调如何定义并导致慢性疼痛的合并情绪障碍。我们期望这是新的 该提案的发现将提供一个新的景观，以了解 慢性疼痛的合并情绪障碍，为全新的治疗可能性提供 慢性疼痛管理。