Novel NOTCH4 Pathway of Asthma Severity in Urban School Children: Clinical Research Center, Boston Children’s Hospital

项目摘要 这个CAUSE应用程序汇集了经验丰富的临床和实验室研究人员在内城哮喘， 临床研究和临床试验、免疫学、遗传学、环境暴露、生物信息学、 数据管理和统计。研究者在实施多中心和 包括哮喘在内的过敏性疾病的单中心临床试验和观察性研究， 美国国立卫生研究院资助临床研究网络，在美国进行疾病机制的基础研究， 以及培训一代又一代的哮喘研究人员 在A部分中，我们证明我们有人员和设施进行哮喘网络范围和临床 研究中心对过敏和哮喘人群招募的市中心儿童进行的特定研究 波士顿儿童医院的哮喘诊所和我们刚刚完成的，以及正在进行的，NIH资助的研究 患有哮喘、过敏性疾病和健康对照的市中心学童。我们有一位经验丰富的 团队，IRB批准的哮喘患者和健康人招募和临床表征方案 控制和基础设施，包括临床研究设施、研究性药房服务、 能够处理、储存和运输人类样本的实验室设施， 一个专注于哮喘25年的研究实验室和一个具有质量控制计划的数据管理设施， 以及将数据上传到NIAID指定的储存库和生物统计支持的能力。 在B部分，我们中心的具体项目借鉴了以前对新的NOTCH 4通路和气道的工作。 炎症，并将利用已经很好地描述了哮喘患者的城市学校人口， 健康对照我们的总体假设是，NOTCH 4信号传导作用于调节气道炎症， 增加哮喘的严重程度和失控的内城学校的孩子。我们的目标是1）测试假设 外周血NOTCH 4 + T细胞亚群的升高定义了哮喘是由 IL-6依赖性机制，赋予更严重或控制不良的表型2）确定 NOTCH 4 + THBE的环境决定因素以及它们如何介导疾病的严重程度和控制，以及3） 研究增加NOTCH 4蛋白表达的调节变体是否与更多的 严重哮喘表型和内型。 该项目将证实我们发现的环境暴露在城市学校中的重要作用， 哮喘儿童的家庭和影响信号传导的调节变体可能被新的 通过环境途径的机制基因。我们将阐明新的机制的生物学基础， 呼吸道炎症，并为未来的生物标志物驱动的方法铺平道路，以告知未来的精确治疗。 我们解决了一个关键的知识差距，减少不成比例的哮喘负担在脆弱的个人。我们 作为一个事业临床研究中心，我们的基础设施和专业知识将为事业做出广泛的贡献。

PROJECT SUMMARY This CAUSE application brings together seasoned clinical and laboratory investigators in inner-city asthma, with expertise in clinical studies and clinical trials, immunology, genetics, environmental exposures, bioinformatics, data management, and statistics. The investigators have long track records in implementing multi-center and single-center clinical trials and observational studies in allergic diseases, including asthma, to the standards of NIH funded clinical research networks, in conducting NIH fundamental research on disease mechanisms in asthma and in training generations of investigators in asthma research In part A we demonstrate that we have the personnel and facilities to conduct asthma network-wide and Clinical Research center-specific research on inner-city children with asthma populations recruited from the allergy and asthma clinics at Boston Children's Hospital and from our just completed, as well as ongoing, NIH-funded studies of inner-city schoolchildren with asthma, allergic diseases and healthy controls. We have a highly experienced team, IRB-approved protocols for recruitment and clinical characterization of asthma patients and healthy controls and 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 asthma and a data management facility with quality control plans, and capability to upload data into the NIAID designated repositories and biostatistical support. In part B our Center specific project draws from previous work on the novel NOTCH4 pathway and airway inflammation and will draw on an already well-characterized urban school population of asthma patients and healthy controls. Our overall hypothesis is that NOTCH4 signaling acts to regulate airway inflammation and increases asthma severity and loss of control in inner-city school children. Our aims are to 1) test the hypothesis that elevated peripheral blood NOTCH4+ Tregs defines a population of patients whose asthma is driven by an IL-6 dependent mechanism that confers a more severe or poorly controlled phenotype 2) determine the environmental determinants of the NOTCH4+ Tregs and how they mediate disease severity and control and 3) investigate whether regulatory variants that increase NOTCH4 protein expression are associated with more severe asthma phenotypes and endotypes. This project will confirm the role of environmental exposures we have found important in urban schools and homes of children with asthma and that regulatory variants that impact signaling may be modified by novel mechanistic gene by environment pathways. We will elucidate novel mechanisms fundamental to the biology of airway inflammation and pave the way for future biomarker driven approaches to inform future precision therapy. We address a critical knowledge gap in reducing disproportionate asthma burden in vulnerable individuals. We will contribute extensively to the CAUSE as a CAUSE-Clinical Research Center, with our infrastructure and expertise.