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

• 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
• 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

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 2型糖尿病（T2D）在美国遭受了近3000万人的折磨，至少50％患有神经系统 包括糖尿病神经病（DN）的并发症。 T2D的代谢变化产生了大量 外周神经损伤通常表现为虚弱的麻木和神经性疼痛。进展 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 并自心，同时也会增加严重伤害的风险。没有有效的DN治疗 对于患者，必须依靠症状管理方案略有效率并具有 燃烧的副作用曲线。需要对DN的新机制进行基础研究以帮助 确定有效的治疗方法。最近的临床研究确定了DN和DN之间的前所未有的关联 糖尿病血脂异常。但是，知识的差距很大 血脂异常调节DN。 Omega-6多不饱和脂肪酸（PUFA）的氧化代谢产物已 通过直接激活急性和炎症性疼痛条件下激活和/或敏感的伤害感受器 TRPV1和TRPA1。但是，没有研究评估其在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将omega-6 pufas氧化为神经活性代谢产物引起的。测试 假设我们将：（1）确定T2D对Omega-6 PUFA诱导的激活或灵敏度的影响 周围传入神经元，（2）确定有助于 T2D中周围传入神经元的激活/敏化。该建议将为角色提供新的见解 DN中的氧化脂质的氧化剂，并将测试异常的Omega-6 PUFA氧化与 T2D中的周围传入神经元功能障碍。这些研究可能会产生一种新的机制 血脂异常改变外周神经元功能，产生神经性疼痛，还包括 确定有效治疗DN的新目标。