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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

基本信息

批准号：
10452996
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
项目类别：
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/10452996
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 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 Maintenance Measures Mediating Methods Molecular Mus Nervous system structure Neurons Neuropathy Nociception Nociceptors Nonesterified Fatty Acids Obesity Pain Paper Pathology Patients Pattern Peripheral Peripheral Nervous System Peripheral Nervous System Diseases Persons Pharmacology 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 cell type chronic neuropathic pain chronic pain diabetic diet-induced obesity dietary dimorphism experimental study genetic technology in vivo innovation insight macrophage male new therapeutic target nociceptive response novel novel therapeutic intervention novel therapeutics pain relief painful neuropathy programs public health relevance receptor response theories therapeutic target tool western diet

项目摘要

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