Mechanisms for Omega-6 Modulation of Primary Afferent Nociceptors

Omega-6 调节初级传入伤害感受器的机制

基本信息

批准号：
10472625
负责人：
Kenneth M Hargreaves
金额：
$ 33.91万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
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：
2019-09-18 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10472625
关键词：
Ablation Afferent Neurons Amyloid beta-Protein Analgesics Animals Arachidonic Acids Autoimmune Diseases Behavioral Biological Cardiovascular Diseases Cell membrane Cellular Membrane Chemicals Cutaneous Data Dependence Diabetes Mellitus Diet Dietary intake Electrophysiology (science)Exhibits Exposure to Fiber Gene Expression Goals Healthcare High Fat Diet Image Isoenzymes Knowledge Lead Lipids Measures Mechanics Mechanoreceptors Mediating Medical Membrane Lipids Methodology Mus Nerve Neurons Nociception Nociceptors Omega-3 Fatty Acids Omega-6 Fatty Acids Outcome Oxides Pain Pain Disorder Patients Persistent pain Phospholipase A2 Phospholipids Play Polyunsaturated Fatty Acids Property Public Health Randomized Recommendation Reporting Research Risk Factors Role Sensory Sex Differences Skin System TRP channel Tamoxifen base chronic painful condition clinical development dietary drug development experimental study inhibitor ketogenic diet knock-down lipidomics non-opioid analgesic novel novel strategies pain relief peripheral pain programs receptor response secondary analysis side effect small hairpin RNA transcriptome sequencing

项目摘要

Although medical recommendations about diet are made for cardiovascular disease and diabetes, this is not the case for most pain disorders. However, diet could be a risk factor for chronic pain conditions as linoleic (LA) and arachidonic (AA) acid are essential omega-6 polyunsaturated fatty acids (ω-6 PUFA), where their cell membrane levels are regulated by dietary intake. Importantly, the oxidized metabolites of LA or AA have potent biological actions in activating targets such as transient receptor potential (TRP) channels, which are expressed on primary afferent nociceptors. Thus, the incorporation and release of omega-6 PUFAs from cellular membranes plays a key role in regulating nociceptor activities, including pain. Our central hypothesis is that dietary omega-6 PUFA-induced increase in nociceptor activities is mediated by the activity of PLA2 subtypes, resulting in activation of neuronal receptors/channels. This is supported by mulitple lines of preliminary data using a robust set of behavioral, electrophysiologic, imaging, and RNAseq methodologies. Aim 1. Determine which subclasses of DRG afferents mediate HFD-induced nociception. We will use six Cre+/--DTA+/- mouse lines generated for the conditional ablation of neurons expressing Nav1.8 (all nociceptors), TrpV1 (nociceptors), CGRP (peptidergic nociceptors), Mrgprd (non-peptidergic nociceptors), TrkC (Aβ low threshold mechanoreceptors (LTMR)) and TrkB (Aδ LTMR fibers) (Table 1). Mice will be fed a High omega-6 PUFA diet (H6D) or a low omega-6 diet (L6D) and behavioral, electrophysiologic and lipidomic outcomes will be measured. (Popular ketogenic diets are different as they are low omega-6 PUFA) Aim 2: Determine the effects of H6D on DRG neuronal membrane lipid content and PLA2 isozyme(s) expression and mechanisms for regulating nociceptor activities. Aim 3: Determine whether switching to a L6D or to a high omega-3:Low omega 6 diet reverses the effects of a H6D on nociception. This project has substantial scientific and medical significance as the central hypothesis predicts that H6D will predispose patients to chronic pain conditions and offers new targets for analgesic drug development.

尽管医学上针对心血管疾病和糖尿病提出了有关饮食的建议，但这并不是然而，对于大多数疼痛疾病来说，饮食可能是慢性疼痛的危险因素，如亚油酸。 (LA) 和花生四烯酸 (AA) 是必需的 omega-6 多不饱和脂肪酸 (ω-6 PUFA)，它们的细胞膜水平受饮食摄入量的调节。重要的是，LA 或 AA 的氧化代谢物具有强效作用。激活瞬时受体电位 (TRP) 通道等靶点的生物作用，在初级传入伤害感受器上表达，因此，omega-6 PUFA 的掺入和释放。细胞膜在调节伤害感受器活动（包括疼痛）方面发挥着关键作用。膳食 omega-6 PUFA 诱导的伤害感受器活性增加是由 PLA2 的活性介导的亚型，导致神经元受体/通道的激活，这是由多行支持的。使用一套强大的行为、电生理、成像和 RNAseq 方法获得的初步数据。目标 1. 确定哪些 DRG 传入神经亚类介导 HFD 引起的伤害感受我们将使用 6 个亚类。 Cre+/--DTA+/- 小鼠系，用于条件性消融表达 Nav1.8 的神经元（全部伤害感受器）、TrpV1（伤害感受器）、CGRP（肽能伤害感受器）、Mrgprd（非肽能伤害感受器）、 TrkC（Aβ 低阈值机械感受器 (LTMR)）和 TrkB（Aδ LTMR 纤维）（表 1）。高 omega-6 PUFA 饮食 (H6D) 或低 omega-6 饮食 (L6D) 以及行为、电生理和脂质组学（流行的生酮饮食有所不同，因为它们的 omega-6 PUFA 含量较低）目标 2：确定 H6D 对 DRG 神经元膜脂质含量和 PLA2 同工酶的影响调节伤害感受器活动的表达和机制。目标 3：确定改用 L6D 或高 omega-3:低 omega-6 饮食是否可以逆转 H6D 关于伤害感受。该项目具有重大的科学和医学意义，因为中心假设预测 H6D 将使患者易患慢性疼痛，并为镇痛药物开发提供新目标。