The Role of Sciatic Nerve Inflammation in Diabetic Neuropathy

坐骨神经炎症在糖尿病神经病变中的作用

基本信息

批准号：
10609436
负责人：
Sara Hakim
金额：
$ 3.55万
依托单位：
HARVARD MEDICAL SCHOOL
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：
2022-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10609436
关键词：
Adipose tissue Affect Afferent Neurons Antibodies Axon C Fiber CCL2 gene Cd68 Chemotactic Factors Clinical Coupled Data Data Set Denervation Development Diabetic Neuropathies Diabetic mouse Distal Exhibits Fiber Generations Genes Genetic Transcription High Fat Diet Human Characteristics Hyperglycemia Hyperlipidemia Immune system Impairment Incidence Infiltration Inflammation Inflammatory Injury Insulin Resistance Kinetics Knockout Mice Knowledge Limb structure Macrophage Mechanics Membrane Metabolic Metabolic dysfunction Metabolic stress Metabolic syndrome Mitochondria Modeling Mus Natural regeneration Nerve Nerve Fibers Nerve Regeneration Neuroglia Neurons Neuropathy Nociceptors Non-Insulin-Dependent Diabetes Mellitus Numbness Obese Mice Obesity Pain Pathogenesis Pathway interactions Patients Pattern Peripheral Nervous System Diseases Phagocytes Prediabetes syndrome Presynaptic Terminals Reaction Recovery Role Secondary to Sensory Signal Transduction Site Skin Source Testing Therapeutic Intervention Traction Type 2 diabetic Up-Regulation Wallerian Degeneration Withdrawal Work afferent nerve axon growth axon injury axonal degeneration cell motility chemokine cytokine density experience feeding human disease improved migration monocyte nerve damage nerve injury nerve supply novel therapeutics prevent recruit reinnervation response response to injury sciatic nerve sciatic nerve injury single nucleus RNA-sequencing transcriptional reprogramming type I and type II diabetes

项目摘要

Abstract Diabetic neuropathy (DN) is characterized by the retraction of sensory axon terminals in the periphery from their targets with a “glove and stocking” pattern. The mechanisms of DN remain though, unclear, impairing successful therapeutic interventions. Unlike type 1 diabetes, type 2 diabetes is accompanied by a systemic metabolic dysfunction that may contribute to the development of DN. Many patients develop neuropathy while pre-diabetic and hyperlipidemia, hyperglycemia, and insulin resistance all impair membrane integrity, axon growth, and mitochondrial motility in sensory neurons. Another important hallmark of the metabolic syndrome is systemic low-grade inflammation involving inflammatory macrophages. Macrophages are major players in Wallerian degeneration and have roles in debris clearance as well as recovery from sciatic nerve injury and regeneration. Whether macrophages in the sciatic nerve contribute or react to diabetic neuropathy is unexplored. I find in preliminary data that pre-diabetic mice exhibit heat hyposensitivity and decreased skin innervation, especially for CGRP+ fibers. I also find that pre-diabetic mice have an increased sciatic nerve inflammation reminiscent of the immediate response to sciatic nerve injury including, CCL2 upregulation and CD68 increase in macrophages. Here, I propose to study if and how sciatic nerve macrophages contribute to diabetic neuropathy or react o axon degeneration. I hypothesize that SCN macrophages contribute to the pathogenesis of type 2 diabetic neuropathy. In the first aim, I will determine whether CCL2-driven recruitment of macrophages to the nerve contributes to the onset of heat hyposensitivity. In the second aim, I will determine whether the sustained increase in CD68+ macrophages/CCL2 signaling in the sciatic nerve contributes to the sustained denervation of the skin of pre-diabetic mice and whether the denervation can be rescued by CCR2 blockade. Finally, I will determine whether small unmyelinated c-fibers undergo injury transcriptional reprogramming and to what extent low-grade inflammation contributes to the DRG neuron transcriptional changes. This study will improve our understanding of if and how the immune system is involved in the development of peripheral neuropathies, which remains largely unknown. In addition, this study will also determine how similar diabetic neuropathy is to sciatic nerve injury models in terms of transcriptional reprogramming. The proposed work could open new therapeutic avenues for pre-diabetic neuropathy, a significant clinical challenge that is only increasing, and will improve our knowledge of how sensory neurons respond to metabolic dysfunction.

抽象的糖尿病神经病（DN）的特征是从其外周中缩回感觉轴突末端具有“手套和库存”图案的目标。不过，DN的机制仍然不清楚，损害成功治疗干预措施。与1型糖尿病不同，2型糖尿病伴有全身代谢可能导致DN发展的功能障碍。许多患者患神经病，而糖尿病前期以及高脂血症，高血糖和胰岛素抵抗都损害了膜完整性，轴突生长和感觉神经元中的线粒体运动。代谢综合征的另一个重要标志是系统性涉及炎症巨噬细胞的低度炎症。巨噬细胞是沃勒里安的主要参与者变性并在碎屑清除以及坐骨神经损伤和再生中恢复中起作用。坐骨神经中的巨噬细胞是否有助于或对糖尿病神经病有效。我在初步数据中发现，糖尿病前小鼠表现出热量低敏性和改善的皮肤神经，特别是对于CGRP+纤维。我还发现糖尿病前小鼠的坐骨神经注射增加让人联想到坐骨神经损伤的立即反应，包括CCL2上调和CD68增加在巨噬细胞中。在这里，我建议研究是否以及坐骨神经神经巨噬细胞如何促进糖尿病神经病或反应轴突退化。我假设SCN巨噬细胞有助于2型糖尿病的发病机理神经病。在第一个目标中，我将确定CCL2驱动的巨噬细胞是否招募到神经有助于热量低敏性发作。在第二个目标中，我将确定是否持续坐骨神经中CD68+巨噬细胞/CCL2信号传导的增加有助于持续的去神经糖尿病前小鼠的皮肤以及是否可以通过CCR2封锁来挽救神经。最后，我会的确定小的无髓纤维是否经历了伤害转录重编程以及在多大程度上低度炎症有助于DRG神经元转录变化。这项研究将提高我们对免疫系统如何以及如何参与发展的理解周围神经病，这在很大程度上未知。此外，这项研究还将确定类似糖尿病神经病是在转录重编程方面对坐骨神经损伤模型。提议工作可以为糖尿病前神经病开放新的治疗途径，这是一个重大的临床挑战，仅是增加，并将提高我们对感觉神经元如何反应代谢功能障碍的了解。