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

特应性皮炎 (AD) 的遗传和微生物调节剂：IL-4Ra R576 多态性患者 AD 严重程度增加的机制以及金黄色葡萄球菌皮肤去定植对 AD 的影响

• 批准号: 9974923
• 负责人: RAIF SALIM GEHA
• 金额: $ 53.07万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9974923
• 关键词: Academic Medical Centers; Adult; Affect; Allergic; Allergic Disease; Antigens; Arginine; Atopic Dermatitis; Biological Markers; Biology; Biometry; Blood; Bone Marrow; Boston; Cells; Child; Childhood; Chimera organism; Clinic; Clinical; Clinical Research; Clinical Trials; Cohort Studies; Cutaneous; Data; Dermatology; Development; Disease; Disease Marker; Financial Hardship; Funding; Gene Expression; General Hospitals; Generations; Genetic; Genetic Polymorphism; Genotype; Glutamine; Hematopoietic; Hospitals; Human; Human Resources; Hypersensitivity; Immune; Immunologics; Immunology; Inflammation; Infrastructure; Institutional Review Boards; Interleukin-13; Interleukin-4; Investigation; Knowledge; Laboratories; Laboratory Research; Link; Massachusetts; Mechanics; Microbiology; Morbidity - disease rate; Mus; Mutation; National Institute of Allergy and Infectious Disease; Observational Study; Patient Recruitments; Patients; Pediatric Hospitals; Pharmaceutical Services; Population; Prevalence; Protocols documentation; Public Health; Quality Control; Records; Research; Research Personnel; Role; Sampling; Seasons; Severities; Severity of illness; Shipping; Signal Transduction; Site; Skin; Skin colonization; Staphylococcus aureus; Testing; Topical application; Training; United States; United States National Institutes of Health; Woman; base; clinical Diagnosis; clinical center; data management; experience; fundamental research; improved; injured; laboratory facility; member; microbial; mortality; mouse model; next generation; novel; patient population; receptor; recruit; repository; research facility; response; skin barrier; statistics

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. !

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，金黄色葡萄酒生物学，皮肤病学和统计学方面的专业知识。 研究人员在实施多中心和单中心临床试验方面有很长的记录 NIH资助的临床研究标准的过敏性疾病（包括AD）的观察性研究 网络，在进行NIH基础研究方面的AD和培训中的疾病机制基础研究 研究人员广告研究 在A部分中，我们证明了我们有人员和设施来进行ADRN网络范围内的ADRN， 从过敏和 波士顿儿童医院的皮肤病学诊所，并在杨百翰和妇女的成人中心合作 医院MAS综合医院和波士顿大学医学中心和医院，从我们的 完成以及正在进行的NIH资助的对过敏性疾病的学童的研究。我们有一个高度 经验丰富的团队，IRB批准的方案，用于招募和临床表征AD患者，这是 包括临床研究设施，研究性药房服务，实验室设施的基础设施 能够处理，存储和运输人类样品，这是最先进的免疫学研究实验室 专注于广告的25年，以及具有质量控制计划的数据管理设施，以及上传的能力 数据到NIAID指定的存储库和生物统计支持。 B部分中的项目将借鉴已经基因型的广告患者的当地人群，以测试 假设IL-4RαR576多态性与AD严重程度的增加和改变有关 表皮和免疫细胞的功能和基因表达。我们还将使用AD的鼠标模型进行测试 表皮和免疫细胞均导致抗原过敏性皮肤增加的假设 IL-4RαR576R多态性的小鼠观察到炎症。 B部分中的第二个项目将检验以下假设，即AD中的金黄色葡萄球菌皮肤非殖民化将减少疾病 严重程度，有利地改变表皮和免疫细胞的功能和基因表达，这有助于 疾病的严重程度。我们还将检验以下假设，即金黄色葡萄球菌的殖民化促进了 使用AD的小鼠模型，抗原驱动的过敏性皮肤感染及其重新激活。 我们的建议将为ADRN作为临床研究部门做出广泛的贡献，并且作为ADRN-CRC， 有助于阐明遗传和微生物修饰剂在AD中的作用。 呢