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

基本信息

批准号：
10704161
负责人：
Rong Grace Zhai
金额：
$ 54.72万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/10704161
关键词：
Affect Afferent Neurons Behavior Bioinformatics Biological Models Cancer Patient Cell Culture Techniques Chemotherapy-induced peripheral neuropathy Computers Data Science Development Dietary Supplementation Dose Dose Limiting Drosophila genus Drosophila inturned protein Enhancers Environment Enzymes Equilibrium Essential Genes Functional disorder Genetic Genetic Models Genetic Transcription Glutamate-ammonia-ligase adenylyltransferase Goals Homeostasis Hypersensitivity Larva Maintenance Mammals Mediating Messenger RNA Metabolism MicroRNAs Modeling Molecular Morphology Natural Compound Neurons Neuropathy Nicotinamide Mononucleotide Nociception Outcome Paclitaxel Pain Pathway interactions Patients Peripheral Peripheral Nervous System Diseases Pharmacology Phase Population Prevention Protein Isoforms Proteins RNA RNA Splicing Regulation Reporter Research Resort Role Sensory Site Symptoms System Therapeutic Therapeutic Agents Tissues Transcriptional Regulation Variant Work bioinformatics tool candidate identification candidate selection chemotherapy chronic neuropathic pain chronic pain design effective therapy efficacy evaluation experience experimental study high throughput screening in vivo in vivo Model innovation mRNA Precursor mRNA Stability neuroprotection neurotoxic novel therapeutics opioid use painful neuropathy pharmacologic proteostasis recreational drug use resilience side effect symptom treatment tool

项目摘要

MicroRNA Regulation of NMNAT-Mediated Neuroprotection Against Peripheral Neuropathy and Chronic Pain 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 behavior and neuronal morphological 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. Our previous work on neuronal maintenance and protection has identified NMNAT (nicotinamide mononucleotide adenylyl transferase), the last enzyme in NAD+ synthesis pathway, as an essential gene that maintains neuronal structural and functional integrity. 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. Within the network of convergent pathways responding to chemotherapy induced peripheral neuropathy, understanding the regulation of NMNAT in both NAD+-metabolism and enhancing neuronal homeostasis will facilitate discovery of neuroprotective strategies in peripheral neuropathy and neuropathic pain.

MicroRNA 对 NMNAT 介导的针对周围神经病变的神经保护的调节慢性疼痛项目概要周围神经病变和神经病变疼痛可由多种遗传和环境引起因素以及治疗性或娱乐性药物的使用。特别是化疗引起的外周血神经病变（CIPN）是标准化疗方案的主要剂量限制性神经毒性副作用。超过 68% 的癌症患者在化疗后会出现神经性症状，这导致很大一部分人口患有慢性疼痛，不得不求助于阿片类药物。现在目前尚无有效的治疗方法，这主要是由于缺乏对体内机制的了解 CIPN 和相关的周围神经病变。最近，我们利用以下方法优化了周围神经病变模型果蝇幼虫概括了化疗的显着行为和神经元形态学方面诱发感觉障碍。我们使用该模型的初步工作发现了一种新机制潜在的周围神经病变，并鉴定出一种具有潜在治疗潜力的神经保护蛋白 NMNAT 减轻神经性疼痛。我们研究的最终目标是揭示内源性机制潜在的周围神经病变并确定神经保护机制和潜在目标促进针对 CIPN 和相关神经性疼痛的新治疗药物的开发。我们之前在神经元维护和保护方面的工作已经确定了NMNAT（烟酰胺单核苷酸腺苷酸转移酶），NAD+合成途径中的最后一个酶，作为必需基因维持神经元结构和功能的完整性。我们的实验室和其他实验室进行了广泛的机制研究发现果蝇和哺乳动物中的 NMNAT 蛋白是最强大和多功能的蛋白之一神经保护因子，NMNAT 表达水平与神经元自我保护呈正相关。防护能力。令人兴奋的是，通过化合物筛选，鉴定出几种天然化合物上调 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 NMNAT RNA 表达的调节天然化合物和 microRNA 在转录、前 mRNA 剪接和 mRNA 稳定性步骤中的作用允许 NMNAT 介导的 NAD+ 代谢和神经元弹性之间的快速动态转变，并且保护感觉神经元免受周围神经病变的影响。在此应用程序中，我们概述了实验旨在 (1) 识别调节伤害性超敏反应的 microRNA，(2) 识别和表征天然化合物调节 NMNAT 表达的分子药理学，以及 (3) 调节 NMNAT 转录调节以增强针对周围神经病变的神经保护。网络内响应化疗引起的周围神经病变的汇聚途径，了解 NMNAT 在 NAD+ 代谢和增强神经元稳态中的调节将有助于发现周围神经病变和神经性疼痛的神经保护策略。