Role of Oxidized Omega-6 Fatty Acid Metabolites in Diabetic Neuropathy

氧化 Omega-6 脂肪酸代谢物在糖尿病神经病变中的作用

基本信息

批准号：
9761186
负责人：
Peter Manning LoCoco
金额：
$ 6.16万
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：
2019-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9761186
关键词：
Acute inflammatory pain Address Afferent Neurons Amputation Attenuated Behavioral Behavioral Assay Biochemical Biopsy Capsaicin Caring Characteristics Clinical Clinical Research Complications of Diabetes Mellitus Data Development Diabetic Neuropathies Diabetic mouse Diet Dyslipidemias Electrophysiology (science)Enzymes Fellowship Fiber Foundations Functional disorder Future Goals Hand High Pressure Liquid Chromatography Human Hyperglycemia Hypersensitivity Immobilization Incidence Individual Inflammatory Injections Injury Intervention Investigation Ketoconazole Knowledge Label Leg Ulcer Lidocaine Limb structure Link Linoleic Acids Lipid Peroxidation Lipids Mass Spectrum Analysis Mechanics Mediating Membrane Metabolic Methodology Mus Nerve Neurologic Neurons Nociception Nociceptors Non-Insulin-Dependent Diabetes Mellitus Numbness Obesity Epidemic Omega-6 Fatty Acids Oxidative Stress Oxides Pain Pain Measurement Pathway interactions Patients Peripheral Peripheral Nerves Pharmacology Play Polyunsaturated Fatty Acids Property Reporting Research Personnel Risk Rodent Role Sensory Skin Study Skills Symptoms TRPV1 gene Testing Time Training Up-Regulation Voriconazole associated symptom base career db/db mouse diabetic effective therapy experience fall risk fatty acid oxidation foot fundamental research inhibitor/antagonist innovation insight leptin receptor mechanical allodynia novel oxidation oxidized lipid painful neuropathy patch clamp peripheral pain response side effect skill acquisition symptom management

项目摘要

ABSTRACT Type 2 diabetes (T2D) afflicts nearly 30 million individuals in the US, with at least 50% suffering from neurological complications that comprise diabetic neuropathy (DN). The metabolic changes in T2D produce substantial peripheral nerve damage that manifests commonly as debilitating numbness and neuropathic pain. Progression of the nerve damage often leads to loss of sensation that can compromise patients’ ability to execute daily tasks and care for themselves, while also increasing risk of severe injury. No effective treatments for DN are available for patients, who instead must rely on symptom management options that are marginally effective and have burdensome side effect profiles. Fundamental research into novel mechanisms of DN is critically needed to help identify effective treatments. Recent clinical studies identified an unprecedented association between DN and diabetic dyslipidemia. However, there are substantial gaps in knowledge regarding the mechanisms by which dyslipidemia regulates DN. Oxidized metabolites of omega-6 polyunsaturated fatty acids (PUFAs) have been shown to activate and/or sensitize nociceptors in acute and inflammatory pain conditions via direct activation of TRPV1 and TRPA1. However, no studies have evaluated their role in DN. Our central hypothesis is that T2D- associated neuropathic pain is due to oxidation of omega-6 PUFAs into neuronally-active metabolites. To test the hypothesis, we will: (1) determine the effects of T2D on omega-6 PUFA-induced activation or sensitization of peripheral afferent neurons, and (2) identify prominent oxidized lipid species that contribute to activation/sensitization of peripheral afferent neurons in T2D. This proposal will provide new insight into the role of oxidized lipids in DN and will test for a causative link between aberrant omega-6 PUFA oxidation and peripheral afferent neuron dysfunction in T2D. These studies may yield a novel mechanism of how diabetic dyslipidemia alters peripheral afferent neuron function to produce neuropathic pain, which also includes identification of new targets for an effective treatment of DN.

抽象的美国有近 3000 万人患有 2 型糖尿病 (T2D)，其中至少 50% 患有神经系统疾病包括糖尿病神经病变 (DN) 在内的并发症 T2D 的代谢变化会产生巨大的影响。周围神经损伤，通常表现为衰弱性麻木和神经性疼痛。神经损伤通常会导致感觉丧失，从而损害患者执行日常任务的能力并照顾自己，同时也增加了严重受伤的风险，目前尚无有效的 DN 治疗方法。对于患者来说，他们必须依靠效果有限且具有一定疗效的症状管理方案迫切需要对 DN 的新机制进行基础研究来提供帮助。最近的临床研究发现 DN 与糖尿病之间存在前所未有的关联。然而，关于糖尿病血脂异常的机制还存在很大的认识空白。血脂异常调节 DN。omega-6 多不饱和脂肪酸 (PUFA) 的氧化代谢物已被证实。在急性和炎症性疼痛情况下，通过直接激活伤害感受器来激活和/或敏化伤害感受器然而，没有研究评估它们在 DN 中的作用，我们的中心假设是 T2D-。相关的神经性疼痛是由于 omega-6 PUFA 氧化成神经元活性代谢物所致。根据假设，我们将： (1) 确定 T2D 对 omega-6 PUFA 诱导的激活或敏化的影响的外周传入神经元，并且（2）识别有助于外周传入神经元在 T2D 中的激活/敏化该提案将为该作用提供新的见解。 DN 中氧化脂质的分析，并将测试异常 omega-6 PUFA 氧化与 T2D 周围传入神经元功能障碍这些研究可能会产生糖尿病如何发生的新机制。血脂异常改变周围传入神经元功能以产生神经性疼痛，其中还包括确定有效治疗 DN 的新靶点。