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

城市学童哮喘严重程度的新型 NOTCH4 途径：波士顿儿童医院临床研究中心

基本信息

批准号：
10592358
负责人：
Talal Amine Chatila
金额：
$ 50.6万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-13 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10592358
关键词：
Address Adult Affect Allergens Allergic Disease Asthma Bioinformatics Biology Biometry Boston Cells Child Childhood Childhood Asthma Chronic Clinic Clinical Clinical Research Clinical Trials Code Cohort Studies Data Databases Disadvantaged Disease Endotoxins Environment Environmental Exposure Environmental Risk Factor Family Functional disorder Funding Future Generations Genes Genetic Genetic Risk Health Health Insurance Home Human Human Resources Hypersensitivity Immune Tolerance Immunology Income Inflammation Inflammatory Infrastructure Institutional Review Boards Interleukin 4 Receptor Interleukin-6 Knowledge Laboratories Laboratory Research Licensing Lung Mediating Minority Groups Molecular Morbidity - disease rate Mus NOTCH4 gene National Institute of Allergy and Infectious Disease Observational Study Outcome Pathway interactions Patient Recruitments Patients Pediatric Hospitals Pharmaceutical Services Phenotype Population Poverty Precision therapeutics Prevalence Process Protocols documentation Public Health Quality Control Records Regulatory T-Lymphocyte Research Research Personnel Risk Factors Role Sampling Schools Seasons Severities Severity of illness Shipping Signal Transduction T-Lymphocyte Testing Tissues Training United States United States National Institutes of Health Urban Population Variant Vulnerable Populations Work airway hyperresponsiveness airway inflammation asthmatic asthmatic patient base biomarker driven clinical center cohort data management disorder control experience fundamental research gene environment interaction genetic variant improved inner city interest laboratory facility modifiable risk mortality next generation novel novel marker novel therapeutic intervention patient population pediatric patients peripheral blood personalized medicine pollutant protein expression recruit repository research facility skills statistics urban area urban children urban school urban setting

项目摘要

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.

项目概要该 CAUSE 应用程序汇集了内城区哮喘领域经验丰富的临床和实验室研究人员，临床研究和临床试验、免疫学、遗传学、环境暴露、生物信息学方面的专业知识，数据管理、统计。研究人员在实施多中心和针对过敏性疾病（包括哮喘）的单中心临床试验和观察性研究，符合 NIH 资助临床研究网络，开展 NIH 疾病机制基础研究哮喘并培训一代又一代的哮喘研究人员在 A 部分中，我们证明我们拥有在整个网络范围内进行哮喘和临床治疗的人员和设施研究中心对从过敏和哮喘中心招募的内城区哮喘儿童进行了专门研究波士顿儿童医院的哮喘诊所以及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内城区学童。我们拥有一支经验丰富的团队，IRB 批准的哮喘患者和健康患者招募和临床特征研究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、储存和运输人体样本的实验室设施，是最先进的免疫学专注于哮喘研究 25 年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 指定存储库和生物统计支持的能力。在 B 部分中，我们中心的具体项目借鉴了之前关于新型 NOTCH4 通路和气道的工作炎症，并将利用已经明确的城市学校哮喘患者群体和健康的控制。我们的总体假设是 NOTCH4 信号传导可调节气道炎症和增加了市中心学童的哮喘严重程度和失控程度。我们的目标是 1）检验假设外周血NOTCH4+ Tregs 升高定义了一群哮喘由以下因素驱动的患者： IL-6 依赖性机制导致更严重或控制不良的表型 2) 决定 NOTCH4+ Tregs 的环境决定因素以及它们如何介导疾病严重程度和控制以及 3) 研究增加 NOTCH4 蛋白表达的调控变异是否与更多相关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和学校中的重要作用。患有哮喘的儿童的家中，影响信号传导的调节变异可能会被新的药物改变环境途径的机械基因。我们将阐明生物学基础的新机制气道炎症，并为未来生物标志物驱动的方法铺平道路，为未来的精准治疗提供信息。我们解决了在减少弱势群体过度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，作为一个临床研究中心，为 CAUSE 做出广泛贡献。