Overall Atopic Dermatitis Research Network

 描述(由申请人提供)：本ADRN申请的主要目的是通过确定特应性皮炎(AD)的不同表型的原因，包括金黄色葡萄球菌(S.aureus)定植、疱疹湿疹(EH)和严重AD，提高我们对皮肤宿主防御机制的理解。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学研究。提出了三个介入临床试验项目，并伴随着机制研究。第一个干预措施将旨在调节皮肤的细菌定植和改善 微生物群移植的皮肤宿主防御。另外两个干预措施将评估在人类AD中阻断Th2/TSLP细胞因子对金黄色葡萄球菌在不同皮肤室(皮内和经皮)的定植和接种反应的影响。三项临床机制研究将旨在描述严重AD表型、易复发EH的AD亚型和金黄色葡萄球菌定植和/或感染的细胞和分子机制。还提出了两种动物方案，通过提供对皮肤宿主对微生物群变化的防御机制的了解，以及比较皮肤和非皮肤接种免疫反应，直接支持临床研究。建议的方案如下：1)AD的靶向微生物组移植；2)抗IL4Ra的Dupilumab(R)对AD宿主-微生物界面的影响；3)经皮接种AD后对Fluzone(R)免疫原性的随机研究；4)确定AD中金黄色葡萄球菌定植决定因素的系统生物学方法；5)综合极端性状分析以了解疱疹湿疹的病因；6)确定不同种族和民族的AD疾病严重程度的决定因素；7)调节金黄色葡萄球菌皮肤免疫对AD小鼠模型的免疫反应；8)屏障对阿尔茨海默病小鼠模型微生物组功能的调控。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的成功完成，将使我们对不同但相关AD表型皮肤中潜在的宿主防御机制下的遗传学、皮肤屏障功能、微生物组、先天和获得性免疫反应的理解发生范式转变。在这一资助期结束时，这些尖端的机制研究将转化为治疗阿尔茨海默病的新方法，阿尔茨海默病是一种仍然难以治疗的疾病，一直没有得到分子特征的描述。

 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.