Genetic and microbial modifiers of Atopic Dermatitis (AD): Mechanisms of increased AD severity in patients with the R576 polymorphism in IL-4Ra and impact of S aureus skin decolonization on AD

该ADRN-CRC应用程序汇集了经验丰富的临床和实验室研究人员， 皮肤炎（AD），具有临床研究、免疫学、金黄色葡萄球菌生物学、皮肤病学和统计学方面的专业知识。 研究者在实施多中心和单中心临床试验方面拥有长期的记录， 过敏性疾病（包括AD）的观察性研究，符合NIH资助的临床研究标准 网络，在进行国家卫生研究院的基础研究疾病机制在AD和培训一代 AD研究中的研究者 在A部分中，我们证明我们拥有进行ADRN网络范围的人员和设施， CRC中心针对儿童和成人AD患者人群的研究，招募自过敏和 波士顿儿童医院的皮肤科诊所和布里格姆妇女医院的成人合作中心 医院马斯总医院和波士顿大学医学中心和医院，并从我们的公正 完成的，以及正在进行的，NIH资助的过敏性疾病学童研究。我们有一个高度 经验丰富的团队，IRB批准的AD患者招募和临床表征方案， 基础设施，包括临床研究设施、研究性药房服务、实验室设施 能够处理、储存和运送人类样本，这是一个最先进的免疫学研究实验室， 专注于AD 25年，拥有质量控制计划的数据管理设施，并能够上传 数据输入NIAID指定的储存库和生物统计支持。 项目I的B部分将利用已进行基因分型的当地AD患者人群， 假设IL-4 R α R576多态性与AD严重程度增加和 表皮和免疫细胞的功能和基因表达。我们还将使用AD的小鼠模型来测试 假设表皮细胞和免疫细胞都有助于增加抗原过敏性皮肤 在具有IL-4 R α R576 R多态性的小鼠中观察到炎症。 项目II的B部分将检验S.金黄色皮肤去殖民化在AD将减少疾病 严重性和有利地改变功能和基因表达的表皮和免疫细胞，有助于 疾病严重程度。我们还将检验S.金黄色葡萄球菌皮肤定植促进了 抗原驱动的过敏性皮肤炎症及其再活化，使用AD小鼠模型。 我们的提案将为ADRN作为临床研究单位做出广泛贡献，并且作为ADRN-CRC将 有助于阐明遗传和微生物修饰剂在AD中的作用。 !

This ADRN-CRC application brings together seasoned clinical and laboratory investigators in atopic dermatitis (AD), with expertise in clinical research, immunology, S aureus biology, dermatology, and statistics. The investigators have long track records in implementing multi-center and single-center clinical trials and observational studies in allergic diseases, including AD, to the standards of NIH funded clinical research networks, in conducting NIH fundamental research on disease mechanisms in AD and in training generations of investigators in AD research In part A we demonstrate that we have the personnel and facilities to conduct ADRN network-wide and CRC center-specific research on pediatric and adult AD patient populations recruited from the allergy and dermatology clinics at Boston Children's Hospital and collaborating adult centers at the Brigham and Women's Hospital Mas General Hospital and Boston University Medical Center and Hospital, and from our just completed, as well as ongoing, NIH-funded studies of schoolchildren with allergic diseases. We have a highly experienced team, IRB-approved protocols for recruitment and clinical characterization of AD patients, an infrastructure which includes clinical research facilities, investigational pharmacy services, a laboratory facility capable of processing, storing and shipping human samples, a state-of-the-art immunology research laboratory with a 25 year focus on AD, and a data management facility with quality control plans, and capability to upload data into the NIAID designated repositories and biostatistical support. Project I in part B will draw on an already genotyped local population of AD patients to test the hypothesis that the IL-4Rα R576 polymorphism is associated with increased AD severity and alterations in the function and gene expression of epidermal and immune cells. We will also use a mouse model of AD to test the hypothesis that both epidermal and immune cells contribute to the increased antigen allergic skin inflammation observed in mice with the IL-4Rα R576R polymorphism. Project II in part B will test the hypothesis that S. aureus skin decolonization in AD will reduce disease severity and favorably alter the function and gene expression of epidermal and immune cells that contribute to disease severity. We will also test the hypothesis that S. aureus skin colonization promotes the development of antigen-driven allergic skin inflammation, and its reactivation, using a mouse model of AD. Our proposal will contribute extensively to the ADRN as a Clinical Research Unit and, as an ADRN-CRC will help elucidate the role of genetic and microbial modifiers in AD. !