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

PPAR 激动剂吡格列酮对特应性皮炎表皮屏障的影响

• 批准号: 8240604
• 负责人: Lisa Ann Beck
• 金额: $ 20.59万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240604
• 关键词: Adult; Agonist; Allergens; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; Atopic Dermatitis; Biological Assay; Celiac Disease; Clinical Trials; Cutaneous; Defect; Diabetes Mellitus; Disease; Epithelial; FDA approved; Food Hypersensitivity; Gene Expression Regulation; Human; Immunologics; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Irritants; Lead; Measures; Mediating; Methods; Mutation; Pathway interactions; Permeability; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Pioglitazone; Play; Population; Predisposition; Prevention; Proteins; Qualifying; Research; Role; Sampling; Simplexvirus; Sinusitis; Skin; Stratum corneum; Structure; Takeda brand of pioglitazone hydrochloride; Testing; Tight Junctions; Translating; Virus; Water; claudin-1 protein; effective therapy; environmental allergen; experience; filaggrin; human disease; improved; in vivo; keratinocyte; novel; novel therapeutics; repaired; response; skin disorder

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. PUBLIC HEALTH RELEVANCE: Atopic dermatitis is the most common inflammatory skin disorder but safe and effective treatments are not available. Currently used treatments are anti-inflammatory, but targeting skin barrier defects that have recently been described in this disease may be more effective. This project investigates the barrier repair effects of a FDA-approved diabetes drug in adults with atopic dermatitis.

描述（由申请人提供）：特应性皮炎（AD）是最常见的皮肤炎性疾病，由Th 2驱动的炎症对环境过敏原的反应引发。研究表明，屏障缺陷使这种强大的免疫反应过敏原。皮肤具有两种屏障结构，角质层（SC）和紧密连接（TJ）。广泛接受的是，SC在AD中是功能障碍的，这是由于脂质的改变和聚丝蛋白以及其他表皮蛋白的获得性或遗传性缺陷。我们最近已经证明，表皮TJ也显着缺陷的AD受试者。这主要是由于关键TJ蛋白claudin-1的表达减少。沉默人角质形成细胞中的claudin-1重现了我们在AD皮肤中观察到的生物电和渗透性缺陷，并且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受试者对皮肤病毒（如HSV）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疗法。过氧化物酶体增殖物激活受体（PPAR）激动剂，如吡格列酮（Actos），在调控上皮细胞增殖，分化，TJ屏障，甚至Th 2途径的组成部分的基因中发挥关键作用。我们发现，吡格列酮增强TJ功能，增加了人角质形成细胞中claudin-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屏障缺陷的AD受试者。我们将使用已建立的和新的方法来可视化和量化双向屏障功能在体内和体外的良好特征的AD受试者。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），以及这是否会降低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，我们拥有大量充分表征的AD人群，以及我们开发的用于测量屏障功能原代人表皮样本的新型测定方法的经验，因此我们具有进行本研究的唯一资格。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，本研究中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。 公共卫生相关性：特应性皮炎是最常见的炎症性皮肤病，但目前尚无安全有效的治疗方法。目前使用的治疗方法是抗炎，但针对最近在这种疾病中描述的皮肤屏障缺陷可能更有效。该项目研究了FDA批准的糖尿病药物对特应性皮炎成人的屏障修复作用。