Controlling Exosome Noncoding RNA Cargo for Enhanced Wound Healing

项目摘要 外泌体已经成为修复不愈合伤口的潜在治疗载体，其继续被用于治疗创伤。 是发病率的重要来源，并对患者和卫生保健造成巨大的经济负担 系统一般。然而，外泌体的治疗效力-以及因此的翻译潜力-对于 创伤修复是有限的，因为外来体含有少量的核酸货物，如微小RNA（miRNA）， 这对于确定外泌体生物活性至关重要。为了克服这种局限性，我们开发了一种 内皮细胞来源的外泌体的新乙醇调节方法。这种方法减少了抗- 在这些外泌体中增加促血管生成的长非编码RNA货物， 血管生成生物活性的总体增加。血管生成功能障碍是不愈合伤口的标志， 因此，这些增强的外来体制剂在伤口修复中具有治疗潜力。我们的团队的 生物工程师和临床医生将测试进一步控制内皮外泌体非编码的方法， 通过环境调节方法（Aim 1）和外源加载的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泌体在切除、糖尿病、 和烧伤创面修复模型（目标3），以确定最有前途的途径，进一步翻译 调查事务所总的来说，这些研究将促进一类新的治疗方法的发展， 无法愈合的伤口，可以造福数百万患者。

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.