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Mechanistic Studies of the Natural Product Nicotinamide Riboside for Relief of Painful Sensory Neuropathy

天然产物烟酰胺核苷缓解疼痛性感觉神经病的机制研究

基本信息

批准号：
10087890
负责人：
DONNA L HAMMOND
金额：
$ 43.52万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10087890
关键词：
Abbreviations Address Afferent Neurons Biosynthetic Proteins Cancer Patient Cancer Survivor Chemotherapy-induced peripheral neuropathy Clinic Data Development Diagnosis Dimensions Distal Dose Dose-Limiting Enzymes Evidence based treatment Female Glutamate-ammonia-ligase adenylyltransferase Healthcare High Pressure Liquid Chromatography Histocytochemistry Human Hypersensitivity Immunohistochemistry In Situ Hybridization Injury Investigation Lead Levocarnitine Acetyl Link Macrophage Activation Maintenance Mammary gland Measurement Measures Mechanics Mediating Methylnitrosourea Natural Products Nature Nerve Nerve Fibers Neurons Neuropathy Niacinamide Nicotinamide Mononucleotide Nicotinamide adenine dinucleotide Nicotinic Acids Oncology Paclitaxel Pain Pathway interactions Peripheral Nervous System Diseases Pharmacotherapy Phase Phosphotransferases Poly(ADP-ribose) Polymerases Population Positioning Attribute Prevention Rattus Research Rodent Model Sirtuins Spinal Ganglia Sterility Supine Position Tactile Testing Time Transcript Translating Vitamins Work avoidance behavior chemotherapy clinically relevant comparative effective therapy efficacious treatment glial activation immunohistochemical markers insight macrophage metabolome mitochondrial dysfunction nerve injury nicotinamide phosphoribosyltransferase nicotinamide-beta-riboside pre-clinical prevent protective effect satellite cell sensory neuropathy spared nerve taxane tool tumor

项目摘要

This project seeks to better understand the mechanisms that underlie painful peripheral neuropathy, and particularly to identify a new strategy to relieve chemotherapy-induced peripheral neuropathies (CIPN) for which there are no efficacious treatments. Indeed, CIPN may be so painful that it is necessary to reduce the dose of agent, delay chemotherapy, or even cease treatment. Furthermore, the peripheral neuropathies may not resolve with time. The dose-limiting nature and the persistence of CIPN are significant health care prob- lems. Much research in the field is driven by hypotheses that loss of intraepidermal nerve fibers (IENF), injury to primary afferent neurons and activation of glial cells and macrophage in the dorsal root ganglion (DRG) underlie taxane-induced CIPN, including a focus on mitochondrial dysfunction. Without an agent that can prevent mechanical hypersensitivity and the aversive dimension of pain, it is not possible to establish that these mechanisms are causative of CIPN or to test the hypothesis that mitochondrial dysfunction is an underly- ing mechanism. We propose to use nicotinamide riboside (NR), a natural product vitamin B3 precursor of NAD+ that can correct mitochondrial dysfunction, as an investigational tool. We show that a dose of NR that increases NAD+ levels can ameliorate the mechanical hypersensitivity and the aversive dimension of pain caused by paclitaxel in tumor-naïve female rats. In contrast, NR does not alleviate sensory neuropathy result- ing from frank nerve injury. This differential effect opens the door to rigorous comparative analyses of the mechanisms by which NR acts to alleviate sensory neuropathy. This proposal will first extend the findings with NR to paclitaxel-induced CIPN in tumor-bearing female rats. Second, it will confirm that NR does not suppress neuropathy in rats with SNI. Third, it will relate the differential actions of NR to injury specific changes in NAD+ biosynthetic enzymes that position DRG neurons in paclitaxel treated rats to make use of NR to correct defi- cits, whereas this pathway is not available after SNI, and support these studies with measurement of NAD+ in the DRG and distal nerve. Fourth, it will characterize the distribution of transcripts and protein for the biosyn- thetic enzymes among the different classes of DRG neurons and determine how they are altered by paclitaxel in tumor naïve and tumor-bearing rats, as well in SNI rats. Fifth, it will determine whether NR prevents the loss of IENF, loss of specific neuron populations, as well as activation of glial cells and macrophages in the DRG. The proposed studies will test the hypothesis that the protective effects of NR are mediated by NAD+ and link this to its protective effects on specific subpopulations of primary sensory neurons, the prevention of IEFN loss, and activation of macrophages and satellite cells in DRG. This work will increase our understanding of the mechanisms that underlie different types of painful sensory neuropathy, possibly guide the development of a new treatment to address a significant unmet need in oncology, and just as importantly provide a rationale as to why this natural product may not be a universal treatment for all types of sensory neuropathy.

该项目旨在更好地了解疼痛性周围神经病变的机制，特别是确定一种缓解化疗诱导的周围神经病（CIPN）的新策略，没有有效的治疗方法。事实上，CIPN可能是如此痛苦，以至于有必要减少剂量的药剂，延迟化疗，甚至停止治疗。此外，周围神经病变可而不是随着时间的推移而解决。CIPN的剂量限制性和持久性是重要的卫生保健问题， lems。该领域的许多研究都是由假设驱动的，即表皮内神经纤维（IENF）的损失，损伤，背根神经节（DRG）内神经胶质细胞和巨噬细胞的活化紫杉烷诱导的CIPN的基础，包括对线粒体功能障碍的关注。如果没有一个特工防止机械性超敏反应和疼痛的厌恶程度，不可能确定这些机制是引起CIPN的原因，或者测试线粒体功能障碍是一个潜在的假设， ing机制。我们建议使用烟酰胺核苷（NR），一种天然产物维生素B3前体， NAD+可以纠正线粒体功能障碍，作为一种研究工具。我们发现，增加NAD+水平可以改善机械超敏反应和疼痛的厌恶维度紫杉醇在未患肿瘤的雌性大鼠中引起。相反，NR不会减轻感觉神经病变的结果- 弗兰克神经损伤。这种差异效应为严格的比较分析打开了大门。 NR缓解感觉神经病变的机制。这项建议将首先扩大调查结果，荷瘤雌性大鼠对紫杉醇诱导的CIPN的NR。其次，它将确认NR不会抑制 SNI大鼠神经病变。第三，将NR的差异作用与损伤特异性NAD+变化联系起来，在紫杉醇治疗的大鼠中定位DRG神经元的生物合成酶， cits，而这一途径在SNI后不可用，并支持这些研究与测量NAD+，背根神经节和远端神经第四，它将表征生物合成的转录本和蛋白质的分布，在不同种类的DRG神经元中合成酶，并确定它们如何被紫杉醇改变在肿瘤初治和荷瘤大鼠中，以及在SNI大鼠中。第五，它将决定NR是否防止损失的IENF，特定神经元群体的损失，以及DRG中神经胶质细胞和巨噬细胞的活化。拟进行的研究将检验NR的保护作用是由NAD+介导的这一假设，这与其对初级感觉神经元的特定亚群的保护作用，IEFN损失的预防，以及DRG中巨噬细胞和卫星细胞的活化。这项工作将增加我们对不同类型的疼痛感觉神经病变的基础机制，可能会指导一个一种新的治疗方法，以解决肿瘤学中显著未满足的需求，同样重要的是，为什么这种天然产品可能不是所有类型的感觉神经病的通用治疗方法。