microRNA regulation of NMNAT-mediated Neuroprotection against Peripheral Neuropathy and Chronic Pain

NMNAT 介导的针对周围神经病变和慢性疼痛的神经保护的 microRNA 调节

• 批准号: 10879437
• 负责人: Rong Grace Zhai
• 金额: $ 6.19万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-16 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10879437
• 关键词: Affect; Afferent Neurons; Award; Behavioral; Cancer Patient; Chemotherapy-induced peripheral neuropathy; Clinical Trials; Computers; Cultured Cells; Data Science; Development; Doctor of Philosophy; Dose Limiting; Drosophila genus; Drosophila inturned protein; Environment; Enzymes; Essential Genes; Family; Functional disorder; Genetic; Genetic Transcription; Glutamate-ammonia-ligase adenylyltransferase; Goals; Graduate Degree; Grant; Health; Homeostasis; Hypersensitivity; Larva; Maintenance; Mammals; Mediating; Metabolism; MicroRNAs; Modeling; Molecular; Natural Compound; Neurons; Neuropathy; Nicotinamide Mononucleotide; Nociception; Paclitaxel; Pain; Parents; Pathway interactions; Peripheral Nervous System Diseases; Pharmacology; Phase; Physiological; Population; Protein Isoforms; Proteins; Puerto Rico; RNA Splicing; Regulation; Research; Research Project Grants; Resort; Role; Sensory; Symptoms; Talents; Testing; Therapeutic; Therapeutic Agents; Training; Transcriptional Regulation; Variant; Work; arm; candidate identification; candidate selection; career development; chemotherapy; chronic pain; design; effective therapy; efficacy evaluation; experience; experimental study; gain of function; graduate student; in vivo; in vivo Model; innovation; innovative technologies; loss of function mutation; mRNA Expression; mRNA Precursor; mRNA Stability; neural; neuroprotection; neurotoxic; novel; novel therapeutics; opioid use; pain model; painful neuropathy; parent project; programs; proteostasis; recreational drug use; recruit; resilience; response; screening; side effect; success; therapeutic miRNA; tool

PROJECT SUMMARY Peripheral neuropathy and neuropathy pain can be caused by a myriad of genetic and environment factors as well as therapeutic or recreational drug use. In particular, chemotherapy-induced peripheral neuropathy (CIPN) is the major dose-limiting neurotoxic side effect of standard chemotherapy regiments. Over 68% of cancer patients experience neuropathic symptoms after chemotherapy, and that contributes to a significant percent of the population that suffer from chronic pain and have to resort to opioid use. Currently there are no effective treatments available, largely due to a lack of understanding of the in vivo mechanisms of CIPN and related peripheral neuropathy. Recently, we have optimized a model of peripheral neuropathy using Drosophila larvae that recapitulates salient behavioral, physiological, and cellular aspects of chemotherapy- induced sensory dysfunction. Our preliminary work using this model has uncovered a new mechanism underlying peripheral neuropathy and identified a neuroprotective protein NMNAT with promising potential for mitigating neuropathic pain. The ultimate goal of our research is to uncover the endogenous mechanisms underlying peripheral neuropathy and to identify neuroprotective mechanisms and potential targets that facilitate the development of new therapeutic agents against CIPN and related neuropathic pain. Extensive mechanistic studies from our lab and others have found NMNAT proteins in Drosophila and mammals to be among the most robust and versatile neuroprotective factors, and a positive correlation between NMNAT expression levels and the neuronal self-protective capacity. Excitingly, from a compound screen, several natural compounds were identified to upregulate NMNAT transcription, and we have collected intriguing preliminary results suggesting that the expression of NMNAT is regulated by microRNAs. We hypothesize that regulation of NMNAT RNA expression by natural compounds and microRNAs at the steps of transcription, pre- mRNA splicing, and mRNA stability allows rapid and dynamic shifting between NMNAT mediated NAD+ metabolism and neuronal resilience and confers protection in sensory neurons against peripheral neuropathy. In this application we outline experiments to (1) identify microRNAs that regulate nociceptive hypersensitivity, (2) identify and characterize the molecular pharmacology of natural compounds in regulating NMNAT expression, and (3) modulate NMNAT transcriptional regulation to enhance neuroprotection against peripheral neuropathy. The objectives for the supplement application are to expand our testing portfolio to include 12 microRNAs and 24 natural compounds. With the recruitment of a full graduate student effort, we will be able to expand our candidate screening portfolio by > 80% and will significantly increase the likelihood of success in identifying candidates with high neuroprotective potential. In addition to the scientific goals, this diversity supplement will also support the PhD training in novel natural compound discovery for pain and fulfill the career development goals of Ms. Natalie Ortiz Vega in the field of natural compound pharmacology.

项目摘要 周围神经病和神经病疼痛可能是由无数的遗传和环境引起的 因素以及治疗或娱乐性药物使用。特别是，化学疗法诱导的周围 神经病（CIPN）是标准化疗方案的主要剂量限制神经毒性副作用。超过 68％的癌症患者在化学疗法后患有神经性症状，这有助于 遭受慢性疼痛并必须诉诸阿片类药物的人群中很大一部分。目前在那里 没有有效的治疗方法，主要是由于对CIPN的体内机制缺乏了解 和相关的周围神经病。最近，我们优化了使用使用的模型 果蝇幼虫概括了化学疗法的显着行为，生理和细胞方面 诱导的感觉功能障碍。我们使用此模型的初步工作发现了一种新机制 周围神经病，并鉴定出具有降低潜力的神经保护蛋白NMNAT 神经性疼痛。我们研究的最终目的是发现内源性机制 周围神经病并确定神经保护机制和潜在靶标，以促进 开发针对CIPN和相关神经性疼痛的新治疗剂。 我们实验室和其他人的广泛机械研究发现了果蝇和 哺乳动物是最坚固和多功能的神经保护因素之一，并且在 NMNAT表达水平和神经元自我保护能力。令人兴奋的是，从复合屏幕上，几个 自然化合物被鉴定为上调NMNAT转录，我们收集了有趣的 初步结果表明NMNAT的表达受microRNA调节。我们假设这一点 自然化合物和microRNA在转录的步骤中调节NMNAT RNA的表达 mRNA剪接和mRNA稳定性允许NMNAT介导的NAD+之间快速而动态的转移 代谢和神经元的弹性，并赋予感官神经元免受周围神经病的保护。 在此应用中，我们概述了（1）确定调节伤害性超敏反应的microRNA， （2）识别和表征自然化合物的分子药理学在调节NMNAT中 表达，（3）调节NMNAT转录调节以增强外周神经保护 神经病。补充申请的目标是将我们的测试组合扩展到包括12 microRNA和24种天然化合物。通过招募全面研究生的努力，我们将能够 将我们的候选人筛选作品集扩大> 80％，并将大大增加成功的可能性。 识别具有高神经保护势的候选人。除了科学目标，这种多样性 补充剂还将支持新颖的自然复合发现中的博士培训，以实现职业 Natalie Ortiz Vega女士在自然复合药理学领域的发展目标。

项目成果

MicroRNA-Mediated Obstruction of Stem-loop Alternative Splicing (MIMOSAS): a global mechanism for the regulation of alternative splicing.

MicroRNA 介导的干环选择性剪接阻碍 (MIMOSAS)：一种调节选择性剪接的全球机制。

• DOI: 10.21203/rs.3.rs-2977025/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Zhai,Rong;Ruan,Kai;Perez,GermanFarinas;Kubat,Miroslav;Liu,Jiaqi;Hofacker,Ivo;Wuchty,Stefan
• 通讯作者: Wuchty,Stefan