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Modulation of Inflammation and Oxidative Stress in Diabetic Wound Healing

糖尿病伤口愈合中炎症和氧化应激的调节

基本信息

批准号：
10811436
负责人：
KENNETH W LIECHTY
金额：
$ 20.18万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-05 至 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10811436
关键词：
Modulation Inflammation Oxidative Stress Diabetic

项目摘要

PROJECT SUMMARY/ABSTRACT: The diabetic wound healing impairment represents a major clinical problem, resulting in prolonged hospitalizations and significant healthcare expenditures. Two-thirds of non- traumatic amputations are preceded by a diabetic wound. The impaired healing of diabetic wounds has been shown to be multifactorial, however, increasing evidence suggests that persistent inflammation contributes to the pathogenesis of diabetic wounds through persistent activation of inflammatory pathways and increased oxidative stress. We have shown that diabetic wounds have increased expression of the proinflammatory cytokines IL-6 and IL-8, and decreased expression of the anti-inflammatory microRNA-146a, which inhibits NFkB activation and downstream IL-6 and IL-8 gene expression. In normal wound healing, macrophages are initially polarized to the proinflammatory M1 phenotype and then transition to the M2 phenotype, which is associated with resolution of inflammation and wound closure. Chronic inflammation and the associated ROS promote persistent proinflammatory M1 macrophage polarization and a failure to transition to the M2 phenotype, which has been implicated in the development of chronic diabetic wounds. We have designed novel cerium oxide nanoparticles (CNPs) that possess ROS scavenging properties and have conjugated them with a miR-146a mimetic, to synergistically target both proinflammatory signaling and ROS. In compelling preliminary data, we have found that one-time treatment of murine diabetic wounds with our novel miR-146a conjugated CNPs (CNP-miR146a) can improve diabetic wound healing, similar to that of non-diabetic wounds at 7 days, and this is associated with decreased inflammation and decreased expression of NOX2. In additional preliminary data, we have shown that CNP-miR146a can also improve wound healing in a streptozotocin porcine diabetes model. The objective of this work is to determine the mechanisms by which CNP-miR146a corrects the diabetic wound healing impairment, and validate this correction and toxicity in a preclinical porcine model. We hypothesize that CNP-miR146a will reduce inflammation and oxidative stress, thus driving macrophage transition from a proinflammatory (M1) to an anti-inflammatory (M2) phenotype and allow for resolution of the chronic inflammatory response and result in enhanced healing. Specific aim 1: To test whether CNP-miR146a corrects the diabetic wound healing impairment by decreasing inflammation and oxidative stress. Specific aim 2: To test whether decreased inflammation and oxidative stress with CNP-miR146a treatment improves healing by decreased proinflammatory (M1) and increased anti- inflammatory/resolving (M2) macrophage polarization. Specific aim 3: To validate that microRNA-146a conjugated CNPs correct the diabetic wound healing impairment and is non-toxic in a preclinical porcine model.

项目总结/摘要：糖尿病伤口愈合障碍代表了一个主要的临床问题，导致长期住院和重大的医疗保健支出。三分之二的非创伤性截肢之前是糖尿病伤口。糖尿病伤口愈合受损，然而，越来越多的证据表明，持续的炎症有助于糖尿病伤口的发病机制是通过持续激活炎症通路和增加氧化应激我们已经发现糖尿病伤口的促炎因子表达增加，细胞因子IL-6和IL-8，以及抗炎microRNA-146 a的表达减少， NF κ B活化和下游IL-6和IL-8基因表达。在正常的伤口愈合中，巨噬细胞最初极化为促炎性M1表型，然后转变为M2表型，与炎症消退和伤口闭合相关。慢性炎症和相关的ROS 促进持续的促炎性M1巨噬细胞极化和未能过渡到M2 表型，其与慢性糖尿病伤口的发展有关。我们设计了具有ROS清除特性并将其缀合的新型氧化铈纳米颗粒（CNP），与miR-146 a模拟物，以协同靶向促炎信号传导和ROS。地迫使初步数据，我们发现用我们的新miR-146 a一次性治疗小鼠糖尿病伤口，缀合的CNPs（CNP-miR 146 a）可以改善糖尿病伤口愈合，类似于非糖尿病伤口的愈合在第7天，这与炎症减少和NOX 2表达减少有关。在额外的初步数据表明，CNP-miR 146 a还可以改善伤口愈合链脲佐菌素猪糖尿病模型。这项工作的目标是确定机制， CNP-miR 146 a纠正糖尿病伤口愈合障碍，并在实验中验证这种纠正和毒性。临床前猪模型。我们假设CNP-miR 146 a将减少炎症和氧化应激，从而驱动巨噬细胞从促炎（M1）转变为抗炎（M2）表型，允许慢性炎症反应的消退并导致增强的愈合。具体目的1：通过以下方式测试CNP-miR 146 a是否纠正糖尿病伤口愈合障碍：减少炎症和氧化应激。具体目的2：测试CNP-miR 146 a是否降低炎症和氧化应激治疗通过减少促炎性（M1）和增加抗炎症性（M2）来改善愈合。炎症/消退（M2）巨噬细胞极化。具体目标3：验证microRNA-146 a缀合的CNP纠正糖尿病伤口愈合在临床前猪模型中是无毒的。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Assessing the bio-stability of microRNA-146a conjugated nanoparticles via electroanalysis.

DOI：
10.1039/d2na00600f
发表时间：
2022-12-20
期刊：
Nanoscale advances
影响因子：
4.7
作者：
通讯作者：

Topical gel-based biomaterials for the treatment of diabetic foot ulcers.

用于治疗糖尿病足溃疡的局部凝胶生物材料。

DOI：
10.1016/j.actbio.2021.10.045
发表时间：
2022-01-15
期刊：
Acta biomaterialia
影响因子：
9.7
作者：
Bardill JR;Laughter MR;Stager M;Liechty KW;Krebs MD;Zgheib C
通讯作者：
Zgheib C

Use of Cerium Oxide Nanoparticles Conjugated with MicroRNA-146a to Correct the Diabetic Wound Healing Impairment.

DOI：
10.1016/j.jamcollsurg.2018.09.017
发表时间：
2019-01
期刊：
Journal of the American College of Surgeons
影响因子：
5.2
作者：
Zgheib C;Hilton SA;Dewberry LC;Hodges MM;Ghatak S;Xu J;Singh S;Roy S;Sen CK;Seal S;Liechty KW
通讯作者：
Liechty KW

Engineered Faceted Cerium Oxide Nanoparticles for Therapeutic miRNA Delivery.