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: 10589788
• 负责人: RAIF SALIM GEHA
• 金额: $ 52.65万
• 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/10589788
• 关键词: Academic Medical Centers; Adult; Affect; Allergic; Allergic Disease; Antigens; Arginine; Atopic Dermatitis; Biological; Biological Markers; Biology; Biometry; Blood; Bone Marrow; Boston; Cells; Child; Childhood; Chimera organism; Clinic; Clinical; Clinical Research; Clinical Trials; Cohort Studies; Collaborations; 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; 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; Schools; 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 center; clinical diagnosis; 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; skills; 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 应用程序汇集了特应性方面经验丰富的临床和实验室研究人员 皮炎（AD），拥有临床研究、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。 研究人员在实施多中心和单中心临床试验方面拥有长期记录， 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，进行 NIH 关于 AD 疾病机制的基础研究和培训一代 AD 研究人员的数量 在 A 部分中，我们证明我们拥有在整个网络范围内开展 ADRN 的人员和设施，并且 CRC 中心针对儿童和成人 AD 患者群体进行的特定研究，这些患者群体是从过敏和 波士顿儿童医院的皮肤科诊所和布莱根妇女医院的合作成人中心 医院 马斯总医院 (Mas General Hospital) 和波士顿大学医学中心及医院 (Boston University Medical Center and Hospital)，以及我们刚刚 已完成的以及正在进行的由美国国立卫生研究院资助的针对患有过敏性疾病的学童的研究。 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、研究药学服务、实验室设施 能够处理、储存和运输人体样本，是最先进的免疫学研究实验室 25 年专注于 AD，拥有具有质量控制计划和上传能力的数据管理设施 数据存入 NIAID 指定的存储库并提供生物统计支持。 B 部分的项目 I 将利用已经进行基因分型的当地 AD 患者群体来测试 假设 IL-4Rα R576 多态性与 AD 严重程度增加和 我们还将使用 AD 小鼠模型来测试表皮和免疫细胞的功能和基因表达。 表皮细胞和免疫细胞均导致皮肤过敏性抗原增加的假设 在具有 IL-4Rα R576R 多态性的小鼠中观察到炎症。 B 部分的项目 II 将检验 AD 中金黄色葡萄球菌皮肤去定植将减少疾病的假设 严重程度并有利地改变表皮和免疫细胞的功能和基因表达，从而有助于 我们还将检验金黄色葡萄球菌皮肤定植促进疾病发展的假设。 使用 AD 小鼠模型研究抗原驱动的过敏性皮肤炎症及其重新激活。 我们的提案将主要为 ADRN 作为临床研究单位做出贡献，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。 ！