Overall Atopic Dermatitis Research Network

 描述（由申请人提供）：本ADRN申请中研究的主要目的是通过确定特应性皮炎（AD）不同表型（包括金黄色葡萄球菌（S.金黄色葡萄球菌）定植、疱疹性湿疹（EH）和严重AD。这些研究将包括评估皮肤屏障，适应性/先天免疫系统对病毒和细菌感染的反应，以及遗传和表观遗传研究。提出了三个干预性临床试验项目及其机制研究。第一次干预的目的是调节皮肤的细菌定植并改善皮肤的生物学特性。 通过微生物组移植进行皮肤宿主防御。另外2项干预措施将评估人AD中Th 2/TSLP细胞因子阻断对S.金黄色葡萄球菌定殖和不同皮肤区室（皮内和经皮）中的疫苗接种应答。三项临床机制研究旨在阐明严重AD表型的细胞和分子机制，以及AD亚型易复发EH和S。金黄色葡萄球菌定植和/或感染。还提出了两种动物方案，通过提供皮肤宿主防御微生物组改变的机制理解，并比较皮肤与非皮肤疫苗接种免疫应答，直接支持临床研究。 拟定方案如下：1）AD中的靶向微生物组移植; 2）Dupilumab（r）（抗IL 4 Ra）对AD中宿主-微生物界面的影响; 3）AD中经皮接种后Fluzone（r）免疫原性的随机研究; 4）确定S. AD中金黄色葡萄球菌定植; 5）综合极端性状分析以了解疱疹性湿疹的病因学; 6）确定不同种族和民族的AD中疾病严重程度的决定因素; 7）在AD小鼠模型中，S.金黄色葡萄球菌; 8）AD小鼠模型中屏障对微生物组功能的控制。 成功完成这6个相互关联的临床项目和2个直接支持人类研究的动物方案，将在我们对遗传学，皮肤屏障功能，微生物组，先天性和适应性免疫反应的理解中产生范式转变，这些免疫反应是不同但相关的AD表型皮肤中宿主防御机制的基础。在本资助期结束时，这些尖端的机制研究将转化为AD的新治疗方法，AD是一种仍然难以治疗且无法进行分子表征的疾病。

 DESCRIPTION (provided by applicant): The primary objective of the studies in this ADRN application is to improve our understanding of mechanisms underlying cutaneous host defense, by determining the cause of different phenotypes of atopic dermatitis (AD) including Staphylococcus aureus (S. aureus) colonization, eczema herpeticum (EH) and severe AD. These studies will include assessment of skin barrier, and adaptive/innate immune system responses to viral and bacterial infections, as well as genetic and epigenetic studies. Three Interventional Clinical Trials Projects with accompanying mechanistic studies are proposed. The first intervention will be aimed at modulating bacterial colonization of the skin and improving the skin host defense by microbiome transplant. The other 2 interventions will assess the effects of Th2/TSLP cytokine blockade in human AD on S. aureus colonization and vaccination responses in different skin compartments (intradermal and transcutaneous). Three Clinical Mechanistic Studies will be aimed at delineating cellular and molecular mechanisms of severe AD phenotypes, and AD subsets prone to recurrent EH, and S. aureus colonization and/or infection. Two animal protocols are also proposed to directly support clinical studies by providing a mechanistic understanding of skin host defense to alterations in microbiome, and comparing cutaneous versus non-cutaneous vaccination immune responses. The proposed protocols are as follows: 1) Targeted Microbiome Transplant in AD; 2) Effect of Dupilumab(r) (anti-IL4Ra) on the Host-Microbe Interface in AD; 3) Randomized Study of Fluzone(r) Immunogenicity after Transcutaneous Vaccination in AD; 4) A Systems Biology Approach to Identify Determinants of S. aureus Colonization in AD; 5) Integrated Extreme Trait Analysis to Understand the Etiology of Eczema Herpeticum; 6) Defining the Determinants of Disease Severity in AD of Different Races and Ethnic Groups; 7) Modulation of the Immune Response to Cutaneous Immunization in a Mouse Model of AD by S. aureus; 8) Control of Microbiome Function by the Barrier in a Mouse Model of AD. Successful completion of these 6 interrelated clinical projects, and 2 animal protocols which directly support the human research, will create a paradigm shift in our understanding of genetics, skin barrier function, microbiome, innate and adaptive immune response underlying host defense mechanisms in the skin of distinct but associated AD phenotypes. At the end of this funding period, these cutting edge mechanistic studies will be translated into new treatment approaches in AD, a disease that remains difficult to treat and that has eluded molecular characterization.