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

项目总结 这项事业应用程序汇集了市中心哮喘领域经验丰富的临床和实验室调查人员， 在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。侦查员在执行多中心和 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，开展美国国立卫生研究院疾病机制的基础研究 哮喘和培训一代代哮喘研究人员 在A部分中，我们展示了我们拥有在全网和临床范围内开展哮喘治疗的人员和设施 研究中心对市中心患有哮喘的儿童进行的研究，这些儿童是从过敏症和 波士顿儿童医院的哮喘诊所和我们刚刚完成的，以及NIH资助的正在进行的研究 对患有哮喘、过敏性疾病和健康对照的市中心学童进行调查。我们有一位经验丰富的 团队，IRB批准的哮喘患者和健康人的招募和临床特征方案 控制和基础设施，包括临床研究设施、研究药房服务、 能够处理、存储和运送人类样本的实验室设施，是一种最先进的免疫学 25年来专注于哮喘的研究实验室和具有质量控制计划的数据管理设施， 以及将数据上传到NIAID指定储存库的能力和生物统计支持。 在B部分，我们中心的具体项目借鉴了先前关于NOTCH4途径和呼吸道的新工作 炎症，并将利用已经很好的特点的城市学校哮喘患者和 健康对照组。我们的总体假设是NOTCH4信号作用于调节呼吸道炎症和 增加市中心学龄儿童的哮喘严重程度和失控。我们的目标是检验这一假说 外周血NOTCH4 Tregs升高定义了一组哮喘患者，他们的哮喘是由 导致更严重或控制较差的表型的IL-6依赖机制决定了 NOTCH4树的环境决定因素及其如何调节疾病严重性和控制3) 研究增加NOTCH4蛋白表达的调控变异是否与更多 重症哮喘的表型和内型。 这个项目将确认环境暴露的作用，我们认为在城市学校和 哮喘儿童的家庭以及影响信号转导的调控变体可能会被新的 环境途径的机械性基因。我们将阐明生物学基础上的新机制。 并为未来的生物标记物驱动的方法铺平道路，为未来的精确治疗提供信息。 我们解决了在减少脆弱个体不成比例的哮喘负担方面的关键知识差距。我们 将凭借我们的基础设施和专业知识，作为一个事业-临床研究中心，为这一事业做出广泛贡献。

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.