Translational study of miR-146a gene therapy for diabetic peripheral neuropathy

 描述（由申请人提供）：周围神经病变是糖尿病的主要并发症。迫切需要开发专门设计用于改善糖尿病后受损周围神经系统的神经功能的有效治疗方法。microRNA-146 a（miR-146 a）参与多种免疫疾病的调控。然而，miR-146 a在糖尿病周围神经病变（DPN）中的作用尚未研究。在一组新的实验中，我们的初步数据显示，静脉注射miR-146 a显著改善了糖尿病小鼠的坐骨神经血管功能、轴突髓鞘形成和外周神经功能，表明miR-146 a可能对DPN的临床治疗具有有益作用。因此，在本申请中，我们试图研究miR-146 a对DPN的治疗作用的潜在机制。我们认为miR-146 a通过改善血管功能和抑制促炎症因子来改善DPN。相关的假设是：1。用化学工程改造的miR-146 a治疗以剂量和治疗窗依赖性方式改善DPN的神经学结局。2. miR-146 a水平升高可抑制II型糖尿病小鼠血管内皮细胞和单核细胞中的靶基因IRAK 1/TRAF 6及其下游促炎因子，从而改善神经血管功能，从而改善周围神经病变。为了研究miR-146 a对神经学结果的影响，将在DPN发作后的不同时间点和剂量用miR-146 a治疗发展严重周围神经病变的II型糖尿病小鼠。为了研究潜在的分子机制，将确定miR-146 a过表达和敲低对介导miR-146 a增强的神经血管功能的靶基因和炎性基因的影响。这些研究具有创新性，将为DPN神经功能障碍的潜在机制提供新的见解，并可能导致新的基于miRNA的基因治疗的发展。

 DESCRIPTION (provided by applicant): Peripheral neuropathy is the major complications of diabetes. There is a compelling need to develop effective therapeutic approaches specifically designed to improve neurological function in the damaged peripheral nervous system after diabetes. MicroRNA-146a (miR-146a) has been implicated in the regulation of multiple immune diseases. However, the role of miR-146a in diabetic peripheral neuropathy (DPN) has not been investigated. In a novel set of experiments, our preliminary data show that intravenous administration of miR-146a remarkably improved sciatic nerve vascular function, axonal myelination and peripheral nerve function in diabetic mice, indicating that miR-146a may have a beneficial effect on the clinical treatment of DPN. In this application, we therefore seek to investigate the mechanisms underlying the therapeutic effects of miR- 146a on DPN. We propose that miR-146a by improving vascular function and suppressing pro-inflammation factors ameliorates DPN. The associated hypotheses are: 1. Treatment with chemically engineered miR-146a improves neurological outcomes in DPN in dose and therapeutic window dependent manners. 2. Elevation of miR-146a levels suppresses its target genes, IRAK1/TRAF6 and their down-stream pro-inflammatory factors in vascular endothelial cells and monocytes of type II diabetic mice, thereby, leading to the improvement of neurovascular function and consequently ameliorating peripheral neuropathy. To investigate the effect of miR- 146a on neurological outcomes, type II diabetic mice which develop severe peripheral neuropathy will be treated with miR-146a at various time points and doses after onset of DPN. To investigate the underlying molecular mechanisms, the effects of miR-146a overexpression and knockdown on target genes and inflammatory genes that mediate miR-146a-enhanced neurovascular function will be determined. These studies are innovative and will provide novel insights into mechanisms underlying the neurological dysfunction of DPN and likely lead to the development of a new miRNA-based gene therapy.