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

点击翻译按钮获取中文摘要

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.