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

 描述(申请人提供)：周围神经病变是糖尿病的主要并发症。迫切需要开发有效的治疗方法，专门设计用于改善糖尿病后受损的周围神经系统的神经功能。MicroRNA-146a(miR-146a)参与多种免疫性疾病的调节。然而，miR-146a在糖尿病周围神经病变(DPN)中的作用尚未被研究。在一组新的实验中，我们的初步数据显示，静脉注射miR-146a显著改善了糖尿病小鼠的坐骨神经血管功能、轴索髓鞘形成和周围神经功能，表明miR-146a可能对DPN的临床治疗具有有利作用。因此，在这一应用中，我们试图研究miR-146a对DPN的治疗作用的潜在机制。我们认为miR-146a通过改善血管功能和抑制促炎因子来改善DPN。相关的假设是：1.化学工程miR-146a治疗以剂量和治疗窗依赖的方式改善DPN的神经学结果。2.上调miR-146a水平可抑制其靶基因IRAK1/TRAF6及其下游促炎症因子在2型糖尿病小鼠血管内皮细胞和单核细胞中的表达，从而改善神经血管功能，从而改善周围神经病变。为探讨miR-146a对周围神经病变的影响，对发生严重周围神经病变的II型糖尿病小鼠在DPN发病后不同时间点、不同剂量给予miR-146a治疗。为了探讨miR-146a过度表达和敲除对介导miR-146a增强神经血管功能的靶基因和炎症基因的影响，我们将研究miR-146a过表达和敲除对靶基因和炎症基因的影响。这些研究是创新的，将为DPN神经功能障碍的潜在机制提供新的见解，并可能导致基于miRNA的新基因疗法的开发。

 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.