The Seibold Lab is leading major National Institutes and Health (NIH) and Department of Defense funded studies that are changing the way we think about asthma and other lung and allergic diseases. An overview of these studies is detailed below.
MAJOR RESEARCH STUDIES
GENETIC CONTROL OF AIRWAY EPITHELIUM GENE EXPRESSION IN CHILDHOOD ASTHMATICS
NIH R01 HL128439‐03
In this study we are performing whole transcriptome sequencing (WTS) on nasal airway brushings from >700 Puerto Rican children with asthma and healthy controls. This WTS data is used to determine the expression of all genes in the genome for these subjects and then integrated with genome-wide genetic variant data to perform expression quantitative trait loci mapping (eQTL). Subsequently, we are fine mapping these eQTLs to uncover those that are asthma-associated in the airway. We are also performing similar eQTL mapping in tracheobronchial airway samples and determining the overlap in upper and lower airway eQTLs. Significant eQTLs are being tested in the Study of Genes-Environments and Admixture in Latino Americans (GALA II) and the Study of African Americans, Asthma, Genes, and Environments (SAGE) cohorts. This project is a collaboration with Dr. Esteban Burchard at UCSF and Dr. Jose Rodriguez-Santana at Centro De Neumologia Pediatrica in San Juan, PR.
GENES, AIR POLLUTION, AND ASTHMA SEVERITY IN MINORITY CHILDREN
NIH R01 MD010443-02
In this study, which centers on the GALA childhood asthma population mentioned above, we are determining how genes interact with air pollution exposures to alter the function of the airway epithelium and, ultimately, both the risk and severity of asthma. Specifically, the Seibold Lab is establishing primary nasal airway epithelial cultures from GALA children to perform culture stimulations with air pollution particulate matter. We are analyzing the whole transcriptome response of cells to these exposures, enabling us to determine genes and networks that are critical in airway epithelial responses to air pollution. We are also using genetic data from these subjects to perform a response eQTL (reQTL) study that will allow us to elucidate how genetics modifies airway epithelial responses to air pollution exposure. The air pollution reQTLs will be tested for association with asthma risk and severity in both GALA and SAGE study cohorts. This work is being carried out in collaboration with Dr. Esteban Burchard at UCSF.
TRANSCRIPTOMIC AND PHARMACOGENETIC ASTHMA ENDOTYPES IN MINORITY CHILDREN
NIH R01 HL135156-01
In this study, we are examining nasal whole transcriptome expression data also from the GALA population to identify asthma airway endotypes, such as type 2-high. We are determining which of these endotypes are associated with severe asthma disease and poor drug response. In addition to the nasal transcriptome data, we are generating blood WTS data on these same subjects which will be analyzed to identify blood biomarkers of nasal airway endotypes. We will use these blood biomarkers to determine the airway endotype of all subjects in the larger GALA and SAGE populations. This will allow us to more powerfully test whether airway endotypes are associated with drug response and severe asthma. We will also investigate the genomic responses to both type 2 cytokines and albuterol using air-liquid interface differentiated airway epithelial cultures from Puerto Rican children, with and without asthma. Lastly, we will determine the genetic basis of Puerto Rican asthma endotypic groups.
DEFINING MOLECULAR PHENOTYPES OF EXACERBATION PRONE ASTHMATICS
NIH P01 HL132821-01A1
This is a P01 grant led by Dr. Dennis Voelker (NJH), Dr. Andy Liu (Children's Hospital Colorado), and Dr. Seibold. For use in the P01 projects, the clinical core, led by Dr. Liu, is recruiting a population of children that are exacerbation-prone asthmatics, exacerbation-resistant asthmatics, and healthy controls. Dr. Liu's project is centered around performing person-level monitoring of environmental exposures in asthmatic subjects to determine which environmental factors (e.g. air pollution, environmental tobacco smoke, allergens, etc.) interact with respiratory viruses to trigger asthma exacerbations. Dr. Voelker's project will examine the preventive and therapeutic potential of pulmonary surfactant components to inhibit respiratory virus infection and inflammatory sequelae that trigger asthma exacerbations. Dr. Seibold's project will examine nasal airway epithelial brushings from study subjects to identify airway endotypes and their genetic determinants, that underlie asthma exacerbations in children. Moreover, the Seibold Lab will directly test how environmental tobacco smoke (ETS) and type 2 cytokines modify the airway epithelial response to human rhinovirus species, and whether this response differs in exacerbation-prone asthmatics. Lastly, we will examine the extent to which genetics underlies asthma exacerbation endotypes and modifies epithelial responses to ETS and cytokine-primed virus infections.
MECHANISMS AND TREATMENT OF DEPLOYMENT-RELATED LUNG INJURY: REPAIR OF THE INJURED EPITHELIUM
Department of Defense W81WH-16-2-0018
This program project grant is led by Dr. Greg Downey (NJH), Dr. Cecile Rose (NJH), Dr. Hong Wei Chu (NJH), Dr. Brian Day (NJH), and Dr. Seibold. The overall goal of this study is to discover how inhalation of airborne particles (‘desert dust’) and other hazardous substances by military personnel deployed to Southwest Asia causes lung damage and to develop strategies to accurately diagnose and repair the injured lung. For this study Dr. Rose is recruiting a population of former deployers and non-deployers with and without asthma and distal lung disease (DLD), from whom both bronchial and nasal airway brushings are being collected. We will perform WTS on these brushings to identify airway endotypes of deployed and non-deployed asthma and DLD. Moreover, we will determine the contribution of particulate matter and genetics to the airway gene expression patterns and endotypes observed in these subjects. We will also investigate how air-liquid interface differentiated airway epithelial cultures generated from these subjects respond to desert dust and whether this dust primes the cells to respond differentially to asthmatic cytokines. Combined, these studies will allow us to identify minimally invasive biomarkers for deployment lung disease diagnosis/risk and to discover disease mechanisms, thereby facilitating the development of new therapeutics.
COLLABORATORS
The highly cross-disciplinary, human-centered research that we conduct cannot be performed in a vacuum, therefore we are a highly collaborative group with many partners in our studies.
Among others, our collaborators include:
Dr. Esteban Burchard (UCSF)
Dr. Jose Rodriguez-Santana (Centro De Neumologia Pediatrica)
Dr. John Fahy (UCSF)
Dr. Erin Gordon (UCSF)
Dr. Andy Liu (Children's Hospital Colorado)
Dr. Dennis Voelker (NJH)
Dr. Greg Downey (NJH)
Dr. Cecile Rose (NJH)
Dr. Eszter Vladar (University of Colorado-AMC)
Dr. Rajesh Kumar (Children's Hospital of Chicago)
Dr. Noah Zaitlin (UCSF)
Dr. Tina Hartert (Vanderbilt University)
Dr. Hong Wei Chu (NJH)
Dr. Tasha Fingerlin (NJH)
Dr. Bill Janssen (NJH)
Dr. Michael Peters (UCSF)
Dr. Fernando Holguin (University of Colorado-AMC)
Dr. Susan Reynolds (Nationwide Children's)
Dr. Rachel Friedman (NJH)
We constantly seek to extend the impact of our work through new collaborations, so feel free to contact us with proposals and ideas on how to work together to do great science!