Controlling Exosome Noncoding RNA Cargo for Enhanced Wound Healing

项目摘要 外切体已经成为修复未愈合伤口的潜在治疗媒介，这些伤口继续 是发病率的重要来源，并给患者和医疗保健带来巨大的经济负担 一般情况下，系统。然而，外切体的治疗效力--因此也就是翻译潜力--对 伤口修复是有限的，因为外体含有少量的核酸货物，如microRNAs(MiRNAs)， 它们对定义外切体生物活性至关重要。为了克服这一限制，我们开发了一种 内皮细胞来源的外切体的新乙醇条件处理方法。这种方法减少了反 并在这些外体中增加促血管生成的长非编码RNA载量，导致 到血管生成生物活性的全面增加。新生血管功能障碍是无法愈合的伤口的标志， 因此，这些增强型外切体制剂在伤口修复方面具有治疗潜力。我们的团队 生物工程师和临床医生将测试进一步控制内皮细胞外显体非编码的方法 通过环境调节方法(目标1)和外源负载的RNA货物和生物活性 技术(目标2)。我们将进一步测试增强的外切体对切除、糖尿病、 和烧伤创面修复模型(目标3)，以确定进一步翻译的最有希望的途径 调查。总体而言，这些研究将促进开发一种新的治疗方法 无法愈合的伤口，可能使数百万患者受益。

Project Summary Exosomes have emerged as potential therapeutic vectors for repair of non-healing wounds, which continue to be a significant source of morbidity and represent a substantial financial burden to patients and health care systems in general. However, the therapeutic potency – and thus the translational potential – of exosomes for wound repair is limited, as exosomes contain low amounts of nucleic acid cargo, such as microRNAs (miRNAs), which are critical to defining exosome bioactivity. Towards overcoming this limitation, we have developed a novel ethanol conditioning approach for endothelial cell-derived exosomes. This method reduces anti- angiogenic miRNA cargo and increases pro-angiogenic long non-coding RNA cargo in these exosomes, leading to an overall increase in angiogenic bioactivity. Angiogenic dysfunction is a hallmark of non-healing wounds, thus these enhanced exosome formulations have therapeutic potential in wound repair. Our team of bioengineers and clinicians will test approaches to further exert control over endothelial exosome non-coding RNA cargo and bioactivity via environmental conditioning approaches (Aim 1) and exogenous loading techniques (Aim 2). We will further test the therapeutic efficacy of enhanced exosomes in excisional, diabetic, and burn injury wound repair models (Aim 3) to identify the most promising avenue for further translational investigations. Overall, these studies will promote the development of a new class of therapeutics for non-healing wounds that could benefit millions of patients.