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

描述（由申请人提供）：特应性皮炎（AD）是最常见的皮肤炎症性疾病，由环境过敏原引起的th2驱动炎症引发。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，由于脂质改变、聚丝蛋白以及其他表皮蛋白的获得性或遗传性缺陷，在AD中SC功能失调。我们最近证明，表皮TJ在AD患者中也有显著缺陷。这主要是由于关键的TJ蛋白claudin-1的表达减少。沉默人角化细胞中的cludin -1，再现了我们在AD皮肤中观察到的生物电和渗透性缺陷，并进一步增强了角化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。过氧化物酶体增殖因子激活受体（PPAR）激动剂，如吡格列酮（Actos），在调节涉及上皮细胞增殖、分化、TJ屏障甚至Th2通路组分的基因中发挥关键作用。我们发现吡格列酮增强了人角质形成细胞的TJ功能，并增加了cludin -1和其他TJ分子的表达。在这里，我们提出了一个试点临床试验，以确定吡格列酮是否会修复AD受试者的屏障缺陷。我们将使用现有的和新颖的方法来可视化和量化在体内和离体的双向屏障功能。本研究的结果将确定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蛋白表达的变化（目的1），以及这是否会减少对已知刺激物的反应（目的2）。鉴于我们在转化人类皮肤屏障研究方面的专业知识，获得大量特征明确的AD人群，以及我们开发的用于测量初级人类表皮样本屏障功能的新检测方法的经验，我们具有开展这项研究的独特资格。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，本研究的观察结果将对部分由上皮屏障缺陷介导的许多其他人类疾病产生影响，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.