The role of cell-specific TLR4 in Diabetic Peripheral Neuropathy

细胞特异性 TLR4 在糖尿病周围神经病变中的作用

• 批准号: 10662277
• 负责人: Michael D Burton
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-08 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662277
• 关键词: Affect; Afferent Neurons; Agonist; Alleles; Animals; Automobile Driving; Biochemical; Biological Assay; Calcium; Cells; Development; Diabetes Mellitus; Diabetic Neuralgia; Diet; Dietary Component; Dietary Factors; Dietary Fats; Dietary Sugars; Disease; Disparate; Dissociation; Electrophysiology (science); Fatty acid glycerol esters; Female; Foundations; Gene Expression; Gene Proteins; Generations; Genetic; Goals; HMGB1 gene; High Fat Diet; Image; Incidence; Individual; Inflammation; Inflammatory; Knock-out; Lead; LoxP-flanked allele; Macrophage; Maintenance; Measures; Mediating; Methods; Molecular; Mus; Nervous System; Neurons; Neuropathy; Nociception; Nociceptors; Nonesterified Fatty Acids; Obesity; Pain; Paper; Pathology; Patients; Pattern; Peripheral; Peripheral Nervous System; Peripheral Nervous System Diseases; Persons; Phenotype; Physiological; Play; Population; Prevention; Production; Publishing; Pyruvaldehyde; Reporting; Research; Resistance; Rodent Model; Role; Saturated Fatty Acids; Sensory; Signal Transduction; Source; Streptozocin; System; TLR4 gene; Therapeutic; Transgenic Organisms; Unhealthy Diet; United States; Work; antinociception; cell type; chronic neuropathic pain; chronic pain; diabetic; diet-induced obesity; dietary; dimorphism; experimental study; genetic technology; in vivo; innovation; insight; male; new therapeutic target; nociceptive response; novel; novel therapeutic intervention; novel therapeutics; pain relief; painful neuropathy; pharmacologic; programs; public health relevance; receptor; response; theories; therapeutic target; tool; western diet

Abstract With an annual occurrence of over 200,000 cases per year, painful diabetic peripheral neuropathy is a leading debilitating disorder in the United States. The mechanisms that underlay its development are highly sought after, because current therapeutics fail to offer relief in over half of patients. A high-fat western diet and obesity play crucial roles in neuronal hyperexcitability that lead to painful diabetic peripheral neuropathy. In certain instances, evidence dissociates diet, diabetes, and obesity, and understanding these disparate mechanisms of action will play a divisive role in identifying therapeutic targets that can modulate neuronal activity. Peripheral sensory neurons express toll-like receptor 4 (TLR4), a receptor whose agonist are dietary free fatty acids, dietary sugar metabolites (methylglyoxal), and danger-associated molecular pattern (DAMPs) expressed during diabetes (HMGB1). This suggests that neurons can be directly activated by TLR4 agonists from various sources to play a role in plasticity leading to painful states during diabetic peripheral neuropathy. Moreover, macrophages are closely situated next to peripheral sensory neurons, express TLR4, and release additional pro-nociceptive factors that sensitize neurons. This study will focus on the peripheral nervous system, utilizing genetic tools to clarify the minimum circuitry necessary to mediate TLR4-dependent activation of DRG nociceptive neurons in developing diet-induced/diabetic neuropathic pain. A key feature of this proposal is that we will study the physiological relevance of TLR4 in specific cell populations in vivo to determine whether nociceptor or macrophage TLR4 is sufficient for the development of diabetic neuropathic pain. We will take advantage of the cre-lox transgenic system offering cell-specific reactivation of TLR4 using newly developed null-reactivatable mice. We have crossed these animals with Nav1.8-cre (sensory neuron) and LysM-cre (macrophage) animals to assess these particular populations in developing neuropathic pain in response to diabetes, diet, or obesity. Our research is aimed at understanding mechanisms driving chronic pain and moving these molecular insights toward new therapeutic strategies for pain alleviation. To accomplish these goals we propose the following specific aims: 1) Determine the role of neuron-specific vs. macrophage-specific TLR4 to develop neuropathic pain and 2) Determine the contribution of dietary components as cell-specific TLR4 agonists to induce sensitization and pain states. These studies will hopefully point to novel therapeutic avenues for the treatment and prevention of diabetic pain by targeting nociceptor and macrophage TLR4 signaling and identify elusive mechanisms through, diet, obesity or diabetes.

摘要 每年发生超过200，000例，疼痛性糖尿病周围神经病变是主要的糖尿病并发症。 在美国的衰弱性疾病。促进其发展的机制受到高度重视 之后，因为目前的治疗方法无法为超过一半的患者提供缓解。高脂肪的西方饮食和肥胖 在导致疼痛性糖尿病周围神经病变的神经元过度兴奋中起关键作用。在某些 在某些情况下，证据将饮食、糖尿病和肥胖分离开来，理解这些不同的机制， 作用将在鉴定可调节神经元活性的治疗靶点方面起分裂作用。外围 感觉神经元表达Toll样受体4（TLR 4），其激动剂是膳食游离脂肪酸， 膳食糖代谢产物（甲基乙二醛），和表达的糖相关分子模式（DAMPs） 糖尿病（HMGB 1）。这表明，神经元可以直接激活TLR 4激动剂从各种 来源发挥作用的可塑性，导致疼痛的国家在糖尿病周围神经病变。此外，委员会认为， 巨噬细胞紧邻外周感觉神经元，表达TLR 4，并释放额外的 致敏神经元的亲伤害感受因子。这项研究将集中在周围神经系统，利用 阐明介导TLR 4依赖性DRG激活所需的最小电路的遗传工具 伤害性神经元在发展饮食诱导/糖尿病神经性疼痛中的作用。 该提案的一个关键特征是，我们将研究TLR 4在特定细胞中的生理相关性。 在体内的群体，以确定伤害感受器或巨噬细胞TLR 4是否足以发展， 糖尿病性神经痛我们将利用cre-lox转基因系统提供细胞特异性 使用新开发的空重活化小鼠重活化TLR 4。我们把这些动物和 Nav1.8-cre（感觉神经元）和LysM-cre（巨噬细胞）动物，以评估这些特定的群体， 糖尿病、饮食或肥胖引起的神经性疼痛。我们的研究旨在了解 驱动慢性疼痛的机制，并将这些分子见解推向新的治疗策略， 减轻疼痛。为了实现这些目标，我们提出了以下具体目标：1）确定 神经元特异性与巨噬细胞特异性TLR 4发展神经病理性疼痛和2）确定的贡献 作为细胞特异性TLR 4激动剂的饮食成分，以诱导致敏和疼痛状态。 这些研究有望为糖尿病的治疗和预防指明新的治疗途径。 疼痛通过靶向伤害感受器和巨噬细胞TLR 4信号传导，并确定难以捉摸的机制，饮食， 肥胖或糖尿病。

项目成果

High-fat diet causes mechanical allodynia in the absence of injury or diabetic pathology.

• DOI: 10.1038/s41598-022-18281-x
• 发表时间: 2022-09-01
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Tierney, Jessica A.;Uong, Calvin D.;Lenert, Melissa E.;Williams, Marisa;Burton, Michael D.
• 通讯作者: Burton, Michael D.