Effect of the PPAR Agonist Pioglitazone on Epidermal Barrier in Atopic Dermatitis

描述(申请人提供)：特应性皮炎(AD)是最常见的皮肤炎症性疾病，由Th2驱动的炎症反应环境过敏原引发。研究表明，屏障缺陷使这种对过敏原的强大免疫反应成为可能。皮肤有两个屏障结构，角质层(SC)和紧密连接(TJ)。人们普遍认为，阿尔茨海默病的SC功能障碍是由于脂质的改变，以及微丝蛋白和其他表皮蛋白的获得性或遗传性缺陷。我们最近已经证明，在AD患者中，表皮TJ也存在显著缺陷。这在很大程度上是由于关键的TJ蛋白claudin-1的表达减少。在人类角质形成细胞中沉默claudin-1，重现了我们在AD皮肤中观察到的生物电学和通透性缺陷，并进一步增强了角质形成细胞对单纯疱疹病毒(HSV)的感染性。后一项发现表明，TJ缺陷也可能是AD患者对HSV等皮肤病毒易感性的原因。因此，迫切需要增加上皮屏障完整性而不仅仅是抑制炎症的治疗方法。过氧化物酶体增殖物激活受体(PPAR)激动剂，如吡格列酮(Actos)，在调节与上皮细胞增殖、分化、TJ屏障甚至Th2途径的组成部分有关的基因方面发挥着关键作用。我们发现，吡格列酮增强了角质形成细胞的TJ功能，增加了Claudin-1和其他TJ分子的表达。在这里，我们建议进行一项试点临床试验，以确定吡格列酮是否可以修复AD患者的屏障缺陷。我们将使用已建立的和新的方法来可视化和量化在具有良好特征的AD受试者体内和体外的双向屏障功能。这项研究的结果将确定PPAR+激动剂对皮肤屏障功能的影响，这如何转化为相关SC和TJ蛋白的表达变化(目标1)，以及这是否会降低对已知刺激物的反应(目标2)。考虑到我们在转译人类皮肤屏障研究方面的专业知识、接触到大量具有良好特征的AD人群以及我们开发的测量屏障功能的原始人类表皮样本的新颖分析经验，我们是唯一有资格进行这项研究的公司。这项研究可能会为预防和治疗这种令人烦恼的疾病带来新的治疗策略。此外，这项研究中的观察结果将对部分由上皮屏障缺陷介导的其他一些人类疾病产生影响，包括炎症性肠病、乳糜泻、鼻窦炎、食物过敏和哮喘。

DESCRIPTION (provided by applicant): Atopic dermatitis (AD) is the most common inflammatory disorder of the skin and is initiated by Th2-driven inflammation in response to environmental allergens. Research suggests that barrier defects enable this robust immunologic response to allergens. The skin has two barrier structures, the stratum corneum (SC) and tight junctions (TJ). It is widely accepted that the SC is dysfunctional in AD due to alterations in lipis and acquired or genetic defects in filaggrin as well as other epidermal proteins. We have recently demonstrated that epidermal TJ are also remarkably defective in AD subjects. This was largely due to reduced expression of the key TJ protein, claudin-1. Silencing claudin-1 in human keratinocytes recapitulated bioelectric and permeability defects that we observed in AD skin, and furthermore enhanced the infectivity of keratinocytes to herpes simplex virus (HSV). This latter finding suggests that TJ defects may also be responsible for AD subjects' susceptibility to cutaneous viruses such as HSV. Therefore, therapies that increase epithelial barrier integrity rather than just suppress inflammation are urgently needed. Peroxisome proliferator-activated receptor (PPAR) agonists such as Pioglitazone (Actos), play a critical role in the regulation of genes involved in epithelial proliferation, differentiation, TJ barrier and even components of the Th2 pathway. We found that Pioglitazone enhanced TJ function and increased the expression of claudin-1 and other TJ molecules in human keratinocytes. Here we propose a pilot clinical trial to determine whether Pioglitazone will repair barrier defects in AD subjects. We will use established and novel methods to visualize and quantify bidirectional barrier function both in vivo and ex vivo in well-characterized AD subjects. The results from this study will determine the effects PPAR + agonists on skin barrier function, how this translates to changes in expression of relevant SC and TJ proteins (Aim 1) and whether this will reduce the response to a known irritant (Aim 2). We are uniquely qualified to perform this study given our expertise in translational human skin barrier research, access to a large, well-characterized AD population, and experience with novel assays to measure barrier function primary human epidermal samples that we developed. This study may lead to new therapeutic strategies for both prevention and treatment of this vexing condition. Additionally, the observations made in this study will have implications for a number of other human diseases mediated in part by epithelial barrier defects including inflammatory bowel disease, celiac disease, sinusitis, food allergy and asthma.