Engineering the release of oxylipins through the skin

项目总结/摘要 肥胖和2型糖尿病在全球范围内急剧增加。最近的数据显示， 自1980年以来增加了一倍多，如果这些趋势继续下去，估计到2030年， 大约一半的美国人口将肥胖，其中25%发展为2型糖尿病。脂肪组织是 是肥胖和2型糖尿病发生和加重的重要部位，因为它是一个关键的内分泌系统， 一种维持能量平衡的器官，最近的研究已经确定了脂因子，或信号 脂质，从脂肪组织释放的分子，可以介导代谢作用。其中一类 脂因子是氧脂素，即发挥代谢作用的氧化脂质代谢物。一种重要的氧脂素， 代谢控制是亚油酸代谢产物12，13-diHOME，其从棕色脂肪组织释放 (BAT)对啮齿动物和人类的寒冷和运动做出反应，并有益地影响葡萄糖和脂肪酸 新陈代谢. 12，13-diHOME增加脂肪酸摄取到棕色脂肪组织，骨骼肌， 在人中，它与循环甘油三酯和BMI呈负相关。但由于 其半衰期非常短，难以维持全身调节，因此其治疗潜力尚未被 完全实现。为了解决这一重要问题，我们开发了一种范式转换方法，以增加12，13- 通过组织纳米转染（TNT）的diHOME，一种具有高翻译效率的非病毒基因递送技术， 潜力TNT递送Ephx 1/2基因，编码产生生物活性1/2，13-diHOME的酶 导致循环中12，13-diHOME的持续全身性增加，并对应于减少的肥胖 并改善新陈代谢健康。在这些拟议的研究中，我们将优化治疗上调 Ephx 1/2通过TNT在临床前模型中的作用，并全面建立了Ephx 1/2的生理学分支。 12，13-diHOME的持续全身性增加，并提供新的治疗方法来对抗肥胖症， 2型糖尿病我们将使用以下两个具体目标来做到这一点：1）确定有效性， 效率，以及Ephx 1/2向皮肤中的基于TNT的递送增加的机制1/2，13- 循环中的diHOME; 2）确定氧化脂质持续增加的生理后果 12，13-TNT的diHOME。拟议的研究有可能提供范式转变的结果， 阐明维持oxlipin上调的新机制，并提供新的治疗方法， 与肥胖和2型糖尿病作斗争。

PROJECT SUMMARY/ABSTRACT Obesity and type 2 diabetes are increasing dramatically worldwide. Recent data has shown that obesity rates have more than doubled since 1980 and if these trends continue unabated, by 2030 estimates predict that approximately half the U.S. population will be obese, with 25% developing type 2 diabetes. Adipose tissue is an important site for initiation and aggravation of obesity and type 2 diabetes because it is a key endocrine organ that functions to maintain energy homeostasis, and recent studies have identified lipokines, or signaling lipids, released from adipose tissue as molecules that can mediate metabolic effects. One class of these lipokines are oxylipins, oxidized lipid metabolites that exert metabolic effects. An important oxylipin for metabolic control is the linoleic acid metabolite 12,13-diHOME, which is released from brown adipose tissue (BAT) in response to cold and exercise in rodents and humans and beneficially impacts glucose and fatty acid metabolism. 12,13-diHOME increases fatty acid uptake into brown adipose tissue, skeletal muscle, and cardiomyocytes, and is negatively correlated with circulating triglycerides and BMI in humans. However, due to its very short half-life, systemic regulation is difficult to maintain and thus its therapeutic potential has not been fully realized. To address this essential issue, we developed a paradigm-shifting approach to increase 12,13- diHOME via tissue nanotransfection (TNT), a non-viral gene delivery technology with high translational potential. TNT delivery of the genes Ephx1/2, coding for the enzymes that make bioactive 12,13-diHOME results in a sustained systemic increase of 12,13-diHOME in circulation and corresponds to reduced adiposity and improved metabolic health. In these proposed studies we will optimize a therapeutic upregulation of Ephx1/2 via TNT in pre-clinical models and comprehensively establish the physiological ramifications of a sustained systemic increase in 12,13-diHOME and provide new therapeutic approaches to combat obesity and type 2 diabetes. We will do this using the following two specific aims: 1) Determine the effectiveness, efficiency, and mechanisms through which TNT-based delivery of Ephx1/2 into the skin increases 12,13- diHOME in circulation and; 2) Determine the physiological ramifications of a sustained increase in the oxylipin 12,13-diHOME by TNT. The proposed studies have the potential to provide paradigm-shifting results and elucidate novel mechanisms to sustain oxylipin up-regulation and providing new therapeutic approaches to combat obesity and type 2 diabetes.