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. !

这种ADRN-CRC应用程序将经验丰富的特应性临床和实验室研究人员聚集在一起 皮炎(AD)，擅长临床研究、免疫学、S金黄色葡萄球菌生物学、皮肤科和统计学。 研究人员在实施多中心和单中心临床试验方面有着长期的记录和 包括阿尔茨海默病在内的变态反应性疾病的观察性研究，符合美国国立卫生研究院资助的临床研究的标准 网络，在NIH进行AD疾病机制的基础研究和培训世代 AD研究中的研究人员 在A部分中，我们证明我们拥有在全网范围内进行ADRN和 针对儿童和成人AD患者人群的CRC中心特定研究招募自过敏和 波士顿儿童医院的皮肤科诊所和布里格姆妇女中心的合作成人中心 医院Mas总医院和波士顿大学医学中心和医院，从我们刚刚 已完成和正在进行的、由美国国立卫生研究院资助的对患有过敏性疾病的学童的研究。我们有一个非常高的 经验丰富的团队，IRB批准的AD患者招募和临床特征方案，以及 基础设施，包括临床研究设施、研究药房服务、实验室设施 能够处理、存储和运输人类样本，一个最先进的免疫学研究实验室 专注于AD 25年，以及具有质量控制计划和上传能力的数据管理设施 将数据输入NIAID指定的储存库和生物统计支持。 B部分的项目I将利用已经分型的当地AD患者群体来测试 假设IL-4RαR576基因多态性与AD严重程度增加和AD的改变有关 表皮细胞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 表皮细胞和免疫细胞共同作用于抗原过敏皮肤的假说 携带IL-4RαR576R多态的小鼠出现炎症反应。 B部分的项目II将测试AD中金黄色葡萄球菌皮肤非殖民化将减少疾病的假设 严重并有利地改变表皮细胞和免疫细胞的功能和基因表达 疾病的严重性。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 抗原驱动的过敏性皮肤炎症，以及它的重新激活，使用AD的小鼠模型。 我们的建议将广泛促进ADRN作为一个临床研究单位，并作为ADRN-CRC将 有助于阐明遗传和微生物修饰物在阿尔茨海默病中的作用。 好了！