Schwann cell derived exosomes improve diabetic peripheral neuropathy in type II diabetic mice

雪旺细胞衍生的外泌体改善 II 型糖尿病小鼠的糖尿病周围神经病变

基本信息

批准号：
10413254
负责人：
Lei Wang
金额：
$ 41.12万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10413254
关键词：
Ablation Affect American Animal Model Axon Blood Glucose Cells Clinical Data Communication Complications of Diabetes Mellitus Data Demyelinations Development Diabetes Mellitus Diabetic mouse Electrons Endosomes Engineering Family member Funding Gene Family Genes Glycosylated Hemoglobin Glycosylated hemoglobin A High Fat Diet Homeostasis Homologous Gene Intravenous Investigation Mediating MicroRNAs Microscopic Molecular Mus Nerve Fibers Nerve Tissue Nervous System Physiology Neurologic Dysfunctions Neurological outcome Neurons Neurophysiology - biologic function Non-Insulin-Dependent Diabetes Mellitus PTEN gene Peripheral Nerves Peripheral Nervous System Diseases Phase I Clinical Trials Physiological Play Proteins Proteolipids RNA Research Role Schwann Cells Semaphorins Somatostatin Source Spinal Ganglia Streptozocin Testing Therapeutic Effect Translations Type 2 diabetic Wild Type Mouse axon injury base clinically relevant db/db mouse design diabetic disability effective therapy exosome improved intercellular communication intravenous administration knock-down liver function mouse model nanovesicle novel novel therapeutic intervention pre-clinical sciatic nerve therapeutically effective transmission process

项目摘要

Abstract: Peripheral neuropathy is one of the major common complications of diabetes. There is a compelling need to develop effective therapeutic approaches specifically designed to improve neurological function caused by diabetic peripheral neuropathy (DPN). Communications between Schwann cells and sciatic nerves of dorsal root ganglia (DRG) neurons maintain homeostasis of peripheral nerve function. Exosomes, endosome-derived nano vesicles carry RNAs and proteins as their molecular cargo. Exosomes mediate intercellular communication by transferring their cargo between source and recipient cells. Our preliminary data showed that treatment of type II diabetes db/db mice with Schwann cell derived exosomes (SC-Exos) remarkably ameliorated neurological dysfunction of DPN, which was associated with significant augmentation of intraepidermal nerve fibers and myelinated axons of the sciatic nerve. We also found that intravenously administered SC-Exos were internalized by Schwann cells and nerve fibers of the sciatic nerve, suggesting that SC-Exos act on Schwann cells and sciatic nerves. Our preliminary data also showed that the SC-Exo treatment did not significantly change blood glucose and glycosylated hemoglobin (HbA1c) levels and liver function; however, importantly, SC-Exos reversed a network of miRNAs and proteins in the sciatic nerve tissues that mediate development of DPN. Based on these preliminary data, using a clinically relevant mouse model of high fat diet/streptozotocin-induced Type 2 diabetes, we propose to test the hypothesis that SC-Exos interact with Schwann cells and sciatic nerves to modulate this network of miRNAs and proteins and thereby ameliorate DPN. We will first examine whether the miRNA cargo of SC-Exo contribute to the therapeutic effect of SC-Exos on DPN. We will then examine whether endogenous miRNAs in Schwann cells and in the sciatic nerve of dorsal root ganglion (DRG) enhance the therapeutic effect of SC-Exo. Subsequently, we will examine whether engineered SC-Exos carrying elevated selected miRNAs to suppress genes that induce axonal injury and demyelination further reduce neurological dysfunction of DPN. Relevance Statement: Diabetic peripheral neuropathy is a major disability affecting millions of Americans. In this proposal, employing clinically relevant animal models of diabetic peripheral neuropathy, we seek to develop a novel therapeutic approach to treat diabetic peripheral neuropathy using exosomes derived from healthy Schwann cells. In this proposal, we will also elucidate the molecular mechanisms by which exosomes are therapeutically effective. This research will potentially provide the essential pre-clinical data for translation of this novel therapeutic approach to a phase 1 clinical trial.

抽象的：周围神经病是糖尿病的主要常见并发症之一。有迫切需要开发专门设计的有效治疗方法，以提高由糖尿病周围神经病（DPN）。雪旺细胞和背根坐骨神经之间的通信神经节神经元保持周围神经功能的稳态。外泌体，内体衍生的纳米囊泡携带RNA和蛋白质作为分子货物。外泌体介导细胞间通信将货物转移到源和受体细胞之间。我们的初步数据表明类型的处理 II糖尿病DB/DB小鼠，具有schwann细胞衍生的外泌体（SC-EXOS）明显改善神经系统 DPN功能障碍，这与表皮内神经纤维的显着增强有关坐骨神经的髓芯轴突。我们还发现，静脉注射的SC-EXO被内在化由坐骨神经的雪旺细胞和神经纤维，表明SC-EXOS作用于Schwann细胞和坐骨神经神经。我们的初步数据还表明，SC-Exo治疗没有显着改变血糖和糖基化血红蛋白（HBA1C）水平和肝功能；但是，重要的是，SC-Exos逆转了介导DPN发育的坐骨神经组织中的miRNA和蛋白质网络。基于这些初步数据，使用高脂肪饮食/链蛋白酶诱导的2型糖尿病的临床相关小鼠模型，我们建议测试SC-EXOS与Schwann细胞和坐骨神经相互作用以调节这一假设 miRNA和蛋白质网络，从而改善DPN。我们将首先检查mirna货物是否 SC-EXO的SC-Exos对DPN的治疗作用有助于。然后，我们将检查内源性是否雪旺细胞中的miRNA和背根神经节（DRG）的坐骨神经增强了治疗效果 SC-Exo。随后，我们将检查是否载有升高选定的miRNA的工程SC-Exos到抑制诱导轴突损伤和脱髓鞘的基因进一步降低了DPN的神经功能障碍。相关性陈述：糖尿病周围神经病是影响数百万美国人的主要残疾。在该提案采用临床相关的糖尿病周围神经病的动物模型，我们寻求发展一种新型的治疗方法，使用来自健康的外泌体治疗糖尿病周围神经病 Schwann细胞。在此提案中，我们还将阐明外泌体是的分子机制治疗上有效。这项研究可能会提供基本的临床前数据，以翻译此 1期临床试验的新型治疗方法。