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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.

项目总结