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

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

糖尿病影响了超过10%的美国人口，另有35%的人有患糖尿病的危险。 多达一半的糖尿病患者会出现慢性疼痛，目前的治疗方法效果不佳。 药物治疗慢性疼痛是糖尿病患者生活质量差的主要原因。虽然我们不 知道糖尿病神经性疼痛的确切原因，增加血浆甲基乙二醛（MGO）水平， 能量生产的化学副产品，与糖尿病的疼痛有关。我们最近的研究表明 MGO诱导伤害感受器的综合应激反应（ISR），使它们成为 超兴奋ISR通过抑制真核生物起始因子2α（eIF 2 α）控制蛋白质合成， 募集eIF 2A到mRNA翻译机器。这导致了对翻译的全局抑制， 促进选择的mRNA转录物的翻译，特别是具有上游开放阅读框的那些。 我们预测，诱导ISR后eIF 2A介导的翻译调节这些细胞的兴奋性。 细胞我们的初步工作表明，ISR参与小鼠和大鼠糖尿病模型以及人类 用MGO处理的感觉神经元。我们的总体假设是ISR引起糖尿病疼痛， ISR通路可用于治疗糖尿病疼痛。因此，在小鼠中进行的初步实验缺乏 eIF 2A的研究表明，eIF 2A的缺失可以保护这些小鼠免受由一种免疫抑制剂引起的诱发性和自发性疼痛。 单次或重复注射MGO。Aim 1将利用小鼠遗传学的力量来产生Nav1.8+ 伤害感受器特异性敲除eIF 2A。我们的目的是证明小鼠伤害感受器中的ISR是MGO-1所必需的。 诱发性和糖尿病性神经病理性疼痛。我们将进一步使用这个模型来检查translatome， 所述mRNA在eIF 2A的影响下翻译，特别是在MGO处理后。目标2： 利用器官捐赠者的培养神经元和神经组织，研究MGO如何改变基因表达 以及用ISR抑制剂（ISRIB）治疗是否可以逆转这些 异常变化我们获得供体组织提供了一个独特的机会来测试这些假设， 模型系统，这是代表的人，这项研究将受益。最后，目标3将采取 II型糖尿病大鼠模型Zucker糖尿病脂肪（ZDF）大鼠的优势，以了解如何靶向 ISR可用于治疗糖尿病疼痛。我们计划使用非阿片类药物治疗，目前在 发展，如ISRIB，在ZDF大鼠。我们的目标是表明，瞄准ISR是一种有效的战略， 预防和逆转糖尿病神经病理性疼痛及其电生理学相关。我们还将表演 对用ISRIB处理的ZDF大鼠进行RNA测序，以检查整个动物中受ISR影响的途径 糖尿病模型通过使用啮齿动物和人类模型，我们将创造一个独特的机会， 使用特定的生物标志物进行治疗，可用于选择患者和监测药物疗效。最终 该项目的目标是促进靶向ISR的非阿片类药物治疗的发展，如ISRIB