Targeting methylglyoxal-induced diabetic neuropathic pain through the integrated stress response

通过综合应激反应针对甲基乙二醛诱发的糖尿病神经性疼痛

• 批准号: 10567294
• 负责人: MUNMUN CHATTOPADHYAY
• 金额: $ 64.81万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-07 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10567294
• 关键词: Advanced Glycosylation End Products; Affect; Afferent Neurons; Affinity Chromatography; Amino Acids; Animal Model; Animals; Behavior; Biological Markers; Biological Models; Blinded; Blood Glucose; Cells; Chemicals; Clinical; Data; Development; Diabetes Mellitus; Diabetic Neuropathies; Disease; Disease Management; Disease Progression; Dose; Drug Monitoring; Electrophysiology (science); Eukaryotic Initiation Factors; Event; Functional disorder; Gene Expression; Genetic; Genetic Transcription; Glycolysis; Goals; Home; Human; Hypersensitivity; Individual; Injections; Intervention; Knock-out; Knowledge; Link; LoxP-flanked allele; Lysine; Mechanics; Mediating; Medical; Messenger RNA; Modeling; Molecular; Molecular Target; Mus; Nerve Fibers; Nerve Tissue; Neurons; Neuropathy; Nociceptors; Non-Insulin-Dependent Diabetes Mellitus; Open Reading Frames; Organ Donor; Pain; Pain management; Pathogenesis; Pathology; Pathway interactions; Patient Selection; Patients; Peripheral Nerves; Persons; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Plasma; Population; Production; Protein Biosynthesis; Publishing; Pyruvaldehyde; Quality of life; Rattus; Repression; Research; Ribosomes; Risk; Rodent Model; Role; Science; Serum; Signal Pathway; Signal Transduction; Spinal Ganglia; Spinal nerve structure; Stress; Techniques; Technology; Testing; Therapeutic; Tissue Donors; Transcript; Transgenic Mice; Transgenic Organisms; Translating; Translations; Type 2 diabetic; Virus Diseases; Western Blotting; Work; biological adaptation to stress; cell type; cellular imaging; chronic pain; clinical efficacy; clinically relevant; design; diabetic; diabetic patient; diabetic rat; disability; drug efficacy; experimental study; human model; inhibitor; inhibitor therapy; insight; mRNA Translation; mouse genetics; new therapeutic target; next generation sequencing; non-opioid analgesic; novel; novel therapeutics; pain behavior; pain model; painful neuropathy; patch clamp; patient stratification; pharmacologic; prevent; protein function; protein misfolding; recruit; response; sex; specific biomarkers; spontaneous pain; stressor; targeted treatment; therapy development; transcriptome sequencing; translational approach; translational model; translatome; Advanced Glycosylation End Products; Affect; Afferent Neurons; Affinity Chromatography; Amino Acids; Animal Model; Animals; Behavior; Biological Markers; Biological Models; Blinded; Blood Glucose; Cells; Chemicals; Clinical; Data; Development; Diabetes Mellitus; Diabetic Neuropathies; Disease; Disease Management; Disease Progression; Dose; Drug Monitoring; Electrophysiology (science); Eukaryotic Initiation Factors; Event; Functional disorder; Gene Expression; Genetic; Genetic Transcription; Glycolysis; Goals; Home; Human; Hypersensitivity; Individual; Injections; Intervention; Knock-out; Knowledge; Link; LoxP-flanked allele; Lysine; Mechanics; Mediating; Medical; Messenger RNA; Modeling; Molecular; Molecular Target; Mus; Nerve Fibers; Nerve Tissue; Neurons; Neuropathy; Nociceptors; Non-Insulin-Dependent Diabetes Mellitus; Open Reading Frames; Organ Donor; Pain; Pain management; Pathogenesis; Pathology; Pathway interactions; Patient Selection; Patients; Peripheral Nerves; Persons; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Plasma; Population; Production; Protein Biosynthesis; Publishing; Pyruvaldehyde; Quality of life; Rattus; Repression; Research; Ribosomes; Risk; Rodent Model; Role; Science; Serum; Signal Pathway; Signal Transduction; Spinal Ganglia; Spinal nerve structure; Stress; Techniques; Technology; Testing; Therapeutic; Tissue Donors; Transcript; Transgenic Mice; Transgenic Organisms; Translating; Translations; Type 2 diabetic; Virus Diseases; Western Blotting; Work; biological adaptation to stress; cell type; cellular imaging; chronic pain; clinical efficacy; clinically relevant; design; diabetic; diabetic patient; diabetic rat; disability; drug efficacy; experimental study; human model; inhibitor; inhibitor therapy; insight; mRNA Translation; mouse genetics; new therapeutic target; next generation sequencing; non-opioid analgesic; novel; novel therapeutics; pain behavior; pain model; painful neuropathy; patch clamp; patient stratification; pharmacologic; prevent; protein function; protein misfolding; recruit; response; sex; specific biomarkers; spontaneous pain; stressor; targeted treatment; therapy development; transcriptome sequencing; translational approach; translational model; translatome

Diabetes affects over 10% of the US population and another 35% are at imminent risk of developing diabetes. As many as half of the diabetic population will develop chronic pain that is poorly treated with current medications. Chronic pain is a major contributor to a poor quality of life in diabetic individuals. While we do not know the exact cause of diabetic neuropathic pain, increases plasma levels of methylglyoxal (MGO), a chemical by-product of energy production, have been correlated with pain in diabetes. We have recently shown that MGO induces the integrated stress response (ISR) in nociceptors, causing them to become hyperexcitable. The ISR controls protein synthesis by repressing eukaryotic initiation factor 2α (eIF2α) and recruiting eIF2A to the mRNA translation machinery. This leads to a global suppression of translation while promoting the translation of select mRNA transcripts, particularly those with an upstream open reading frame. We predict that eIF2A-mediated translation following the induction of ISR regulates the excitability of these cells. Our initial work shows that the ISR is engaged in mouse and rat models of diabetes as well as human sensory neurons treated with MGO. Our overarching hypothesis is that the ISR causes pain in diabetes and that the ISR pathway can be targeted for treating pain in diabetes. As such, initial experiments in mice lacking eIF2A show that the loss of eIF2A protects these mice against evoked and spontaneous pain caused by a single or repeated MGO injections. Aim 1 will harness the power of mouse genetics to generate Nav1.8+ nociceptor-specific knockout of eIF2A. We aim to show that the ISR in mouse nociceptors is required for MGO- evoked and diabetic neuropathic pain. We will further use this model to examine the translatome and identify which mRNAs are translated under the influence of eIF2A, especially after MGO treatment. For Aim 2, we will use cultured neurons and nervous tissues from organ donors to find out how MGO changes gene expression and excitability of human neurons and whether treatment with an ISR inhibitor (ISRIB) can reverse these aberrant changes. Our access to donor tissue presents a unique opportunity to test these hypotheses in a model system that is representative of the people that this research will benefit. Finally, Aim 3 will take advantage of a rat model of type II diabetes, the Zucker Diabetic Fatty (ZDF) rats, to understand how targeting the ISR can be used to treat diabetic pain. We plan to use non-opioid therapies that are currently in development, such as ISRIB, in the ZDF rats. We aim to show that targeting the ISR is an effective strategy for preventing and reversing diabetic neuropathic pain and its electrophysiology correlates. We will also perform RNA sequencing on ZDF rats treated with ISRIB to examine pathways influenced by ISR in a whole animal model of diabetes. By using rodent and human models we will create a unique opportunity to clinically model therapies with a specific biomarker that can be used to select patients and monitor drug efficacy. The ultimate goal of this project is to promote the development of non-opioid therapies targeting the ISR, such as ISRIB

糖尿病会影响美国人口的10％以上，而另外35％的糖尿病迫在眉睫的糖尿病风险。 多达一半的糖尿病人群会出现慢性疼痛，而这种疼痛的治疗不佳 药物。慢性疼痛是糖尿病患者生活质量差的主要因素。虽然我们没有 知道糖尿病神经性疼痛的确切原因，增加了血浆水平的甲基甘氨酸（MGO），A 能源产生的化学副产品与糖尿病的疼痛有关。我们最近显示了 MGO影响伤害感受器的综合应力反应（ISR），使它们成为 过度可观。 ISR通过反映真核起始因子2α（EIF2α）和 招募EIF2A到mRNA翻译机械。这导致了全球翻译的压制 促进精选的mRNA转录本的翻译，尤其是那些具有上游开放式阅读框的翻译。 我们预测EIF2A介导的ISR诱导后的翻译会调节这些兴奋 细胞。我们最初的工作表明，ISR参与了糖尿病的小鼠和大鼠模型以及人类 用MGO处理的感觉神经元。我们的总体假设是ISR会导致糖尿病疼痛 ISR途径可以用于治疗糖尿病的疼痛。因此，在缺乏小鼠的初始实验 EIF2A表明，EIF2A的损失可保护这些小鼠免受诱发和赞助的痛苦。 单次或重复的MGO注射。 AIM 1将利用鼠标的力量生成NAV1.8+ EIF2A的特异性敲除。我们的目的是表明MGO-需要小鼠伤害感受器中的ISR- 诱发和糖尿病神经性疼痛。我们将进一步使用此模型检查翻译并确定 在EIF2A的影响下，尤其是在MGO治疗后，将mRNA翻译成这种mRNA。对于目标2，我们将 使用器官捐献者的培养神经元和神经组织来了解MGO如何改变基因表达 人类神经元的激动人心以及用ISR抑制剂（ISRIB）治疗是否可以扭转这些 异常变化。我们获得供体组织的访问提供了一个独特的机会来检验这些假设 代表这项研究将受益的人的模型系统。最后，AIM 3将采取 II型糖尿病的大鼠模型的优势，Zucker糖尿病脂肪（ZDF）大鼠，以了解靶向 ISR可用于治疗糖尿病疼痛。我们计划使用目前正在中的非阿片类药物疗法 在ZDF大鼠中的发展，例如Isrib。我们的目的是表明，针对ISR是一个有效的策略 防止和逆转糖尿病神经性疼痛及其电生理学的相关性。我们也会表演 用ISRIB处理的ZDF大鼠的RNA测序检查整个动物的ISR影响的途径 糖尿病模型。通过使用啮齿动物和人类模型，我们将创建一个独特的机会来临床建模 具有特定生物标志物的疗法，可用于选择患者并监测药物效率。最终 该项目的目标是促进针对ISR的非阿片类药物疗法的发展，例如Isrib