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：
10210940
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/10210940
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 IL4R gene Immune Tolerance Immunology Income Individual Inflammation Inflammatory Infrastructure Institutional Review Boards Interleukin 4 Receptor Interleukin-6 Investigation Knowledge Laboratories Laboratory Research Licensing Lung Mediating Minority Groups Molecular Molecular Genetics 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 Work airway hyperresponsiveness airway inflammation asthmatic asthmatic patient base biomarker-driven clinical center cohort data management disorder control experience fundamental research gene environment interaction 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 statistics urban area urban children urban school urban setting

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 IL4R gene Immune Tolerance Immunology Income Individual Inflammation Inflammatory Infrastructure Institutional Review Boards Interleukin 4 Receptor Interleukin-6 Investigation Knowledge Laboratories Laboratory Research Licensing Lung Mediating Minority Groups Molecular Molecular Genetics 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 Work airway hyperresponsiveness airway inflammation asthmatic asthmatic patient base biomarker-driven clinical center cohort data management disorder control experience fundamental research gene environment interaction 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 statistics urban area urban children urban school urban setting

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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.

项目摘要此原因应用汇集了内城哮喘的经验丰富的临床和实验室研究者，在临床研究和临床试验，免疫学，遗传学，环境暴露，生物信息学方面的专业知识，数据管理和统计数据。调查人员在实施多中心方面有很长的记录和在包括哮喘在内的过敏性疾病中的单中心临床试验和观察性研究符合标准 NIH资助了临床研究网络，在进行NIH的基础研究上哮喘和哮喘研究中的研究人员的培训在A部分中，我们证明了我们有人员和设施来进行哮喘在网络范围内和临床上进行从过敏和波士顿儿童医院的哮喘诊所以及我们刚刚完成以及正在进行的NIH资助研究内城学童患有哮喘，过敏性疾病和健康对照。我们有一个经验丰富的团队，IRB批准的方案，用于招募和哮喘患者的临床表征和健康控制和基础设施，包括临床研究设施，研究性药房服务，能够处理，存储和运输人类样品的实验室设施，这是一种最先进的免疫学研究实验室25年专注于哮喘和具有质量控制计划的数据管理机构，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，我们的中心特定项目从小说Notch4 Pathway和Airway的先前工作中获取炎症，并将吸引已经有充分表现的哮喘患者的城市人口健康控制。我们的总体假设是Notch4信号传导可调节气道炎症和增加城市学童的哮喘严重程度和失去控制。我们的目的是1）检验假设升高的外周血缺口+ Tregs定义了哮喘由 IL-6的依赖机制，赋予更严重或控制不良的表型2）确定 Notch4+ Treg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Notch4蛋白表达的调节变体是否与更多有关严重的哮喘表型和内型。该项目将确认我们发现在城市学校和哮喘儿童的房屋和影响信号传导的调节变体可以通过新颖机械基因通过环境途径。我们将阐明针对生物学基础的新型机制气道炎症并为未来的生物标志物驱动方法铺平了道路，以告知未来的精确疗法。我们解决了减轻弱势群体哮喘负担不成比例的批判性知识差距。我们将在我们的基础设施和专业知识的情况下为事业做出广泛的贡献。