Fellows in Pediatric Pulmonology pursue a research project during the second and third years of their training. This project can involve educational, clinical, translational or basic science research. Selection of a project is guided by consultation with the Fellowship Director, Associate Fellowship Director, the Division Chief, and other members of the Division. The goal is to have fellows choose an area of research that interests them and also provides strong mentorship.
General Research Activities
The BCH Division of Pulmonary Medicine is actively engaged in a wide range of basic, translational, clinical and educational research initiatives developed to advance our understanding of pediatric lung disease that will ultimately lead to new diagnostic and therapeutic strategies for our patients. Supported by more than $8.0 million in awarded research funds this past year, the Division has published 123 peer-reviewed manuscripts in 71 academic journals, including the New England Journal of Medicine, the American Journal of Respiratory and Critical Care Medicine, the American Journal of Respiratory Cell and Molecular Biology, Nature Communications, Lancet Respiratory Medicine, the Journal of Allergy and Clinical Immunology, the European Respiratory Journal, the Journal of Cystic Fibrosis, and many others.
The Division’s laboratories occupy 6,650 square feet of space on the 4th floor of the John Enders Research Building of Boston Children’s Hospital. The division labs also house six NIH-supported pulmonary investigators. As members of Boston Children’s Hospital and Harvard Medical School, our fellows have access to all our institutions’ core facilities, including a state-of-the-art animal facility, a Cell Imaging and Phenotyping Core (with access to two confocal microscopes, multichannel flow cytometers, and other imaging and cell sorting platforms), and a transgenic animal core. To make research more accessible to our fellows and all our faculty, the Division has in place multiple resources to assist with study organization and grant development including a dedicated grants administrator, a Translational Research Operations Manager, a Clinical Research Manager overseeing clinical trials, a biostatistician, a bioinformatics and data management team, and a number of Research Assistants and Research Coordinators.
Our Division is a world-leader in conducting clinical trials in pediatric populations. This is possible due to the extraordinary work of our Clinical Trials Group, Directed by Dr. Hank Dorkin. Staffed by our Clinical Research Manager and research personnel, this team conducts at any given time between 15 and 30 clinical trials, including studies in CF, childhood interstitial lung disease, asthma, Primary Ciliary Dyskinesia, Pulmonary Artery Hypertension, and Bronchopulmonary Dysplasia. The goal is eventually to have clinical trials in all phases of pediatric pulmonary medicine.
Collaborative research arrangements within the Harvard Medical area are extensive and include the Divisions of Newborn Medicine, Immunology, Allergy, Gastroenterology, Informatics, and others within Boston Children’s Hospital; the Respiratory Division of Brigham & Women’s Hospital; the Physiology Department of the Harvard School of Public Health; Harvard Medical School and the Channing Laboratories at Brigham and Women’s Hospital. The research progress of the fellow is monitored and facilitated through biannual presentations before the fellow’s Scholarship Oversight Committee. In addition to selecting a research project, several fellows in the Division have completed additional courses of study during their fellowship years, including obtaining Masters degrees in Public Health, Ethics, Bioinformatics and Medical Science.
The Division of Pulmonary Medicine is highly competitive for grant external support, with numerous successful applications this year to the National Institutes of Health (NIH), the American Thoracic Society (ATS), the Cystic Fibrosis Foundation (CFF), and the National Organization for Rare Diseases (NORD), among others.
Faculty grant awards (2019-2020)
Ke Yuan: ATS Aldrighetti Research Award for young Investigators (ATS)
Lung Pericytes: A Novel Source of Pathogenic Smooth Muscle Cells in PAH (Francis Family Foundation)
Benjamin Raby: Pulmozyme to Improve COVID-19 ARDS outcomes (MassCPR)
John Kennedy: Program for Adult Care Excellence (CF Foundation)
Greg Sawicki: 2020 Program for Patient Safety and Quality Telehealth Grants Program (BCH).
Ahmet Uluer: Assessment of contraceptive safety and effectiveness in CF (University of Washington/CFF Foundation)
Levent Midyat: Whitetulip Global Health Grant (Whitetulip Health Foundation)
Tregony Simoneau: Creating an Asthma Network: Improving Asthma Management (Connecticut Children’s Medical Center/CIGNA)
Gaffin/Simoneau: Medical Staff Organization Innovation Award (BCH internal)
Ruby Wang: Using induced pluripotent stem cells to model long-term nonprogressive phenotype associated with F508del CFTR mutations (Gilead)
Pulmonary Fellow grant awards:
Dorothy Curran: 1st Year Fellowship Award (CF Foundation)
Jaclyn Davis: 2nd Year Fellowship Award (CF Foundation)
Alexandra Kass: 3rd year fellowship award (CF Foundation)
Ryan Perkins: Developing Value Based Care in CF (CF Foundation)
Sigfus Gunnlaugsson ATS Aspire Fellowship (ATS)
Fran Flanagan: NORD ACDMPV Research Grant (NORD)
Eleanor Muise: NIH Loan Repayment Award. Establishment of a Reliable and Translatable Metric to Score Tracheobronchomalacia in Children with Esophageal Atresia with or without Tracheoesophageal Fistula
Current Research Programs
Pulmonary Genetics Program
Dr. Raby is a genetic epidemiologist known internationally as an expert on the genetics and genomics of asthma, and as a leader in the integration of genetic diagnostics in the clinical practice of pulmonary medicine. He leads an active NIH-funded laboratory that combines population-based integrative genomics with functional genetics to define the molecular determinants of asthma. He has been continuously NIH funded for 16 years and his laboratory is currently supported by four NIH R01 awards. Most recently, Dr. Raby’s group has published new findings demonstrating the importance of activation of the TREM-1 signaling pathway in poorly controlled and severe asthma (now the most replicated gene expression signature of poor asthma control) and the value of screening at-risk relatives of patients with ILD for pre-clinical evidence of ILD. Current projects are focused on understanding the functional mechanisms by which asthma variants confer disease, single-cell RNA-sequencing and biomarker studies in poor asthma control, gene mapping of rare childhood lung disease, and the development of novel computational approaches for the study of complex genetic disorders.
Syndecans- Dr. Pyong Park
Dr. Pyong Park is an authority on the syndecans – extracellular matrix proteins that regulate the anti-inflammatory activity of mesenchymal stem cells (MSCs) in acute lung injury. Most recently, he and his team discovered that glypicans modulate the pathogenesis of pneumonia. His team is currently pursuing the molecular and cellular mechanisms of how syndecans and glypicans function in these manners.
Pluripotent Stem Cells- Dr. Ruobing Wang
Dr. Ruobing Wang is developing approaches to use induced pluripotent stem cells (iPSC) and CRISPR-cas9 gene-editing tools to model disease-relevant immune-epithelial interactions in Cystic Fibrosis (CF). Using samples obtained from CF patients with extreme phenotypes of lung function decline, Dr. Wang has derived 19 viable iPSC lines, has CRISPR-corrected the mutant CFTR gene in 5, and has successfully developed a cell-based model based on in vitro differentiation of patient derived iPSCs to 1) airway epithelium both as 3D-organoids and 2D pseudostratified epithelium plated on air-liquid interface, and 2) functional putative macrophages. The iPSC-airway epithelium grown as 3D organoid captures CF phenotype and has been demonstrated to be a useful platform to test for drug response. The iPSC-airway epithelium grown as 2D pseudostratified layer on air-liquid interface is capable of tight junction barrier formation and mucociliary differentiation. Recently, she has shown that this platform is useful to model cystic fibrosis by demonstrating restoration of Cl- activities in CF iPSC after correction of CFTR via Ussing chamber assay.
Computational Biology- Dr. Sung Chun
Dr. Sung Chun is a geneticist and computational biologist with an interest in complex trait
genetics. He has developed approaches for co-localization of clinical phenotype and regulatory genetic (eQTL) associations and for using polygenic risk scores in the study of pulmonary disease. Current projects include applying these approaches in a clinical setting to improve risk stratification among at-risk relatives of patients with ILD, rare variant mapping in childhood interstitial lung disease, and genome-wide association studies in Eosinophilic Granulomatosis and Polyangiitis (EGPA, formerly called Churg-Strauss Syndrome). Dr. Chun and his team provide bioinformatic and statistical support to fellows and faculty across the division.
Vascular Biology- Dr. Ke Yuan
Dr. Ke Yuan was recently recruited from Stanford University as our newest faculty member. She is a vascular biologist whose research focuses on the role of the lung pericyte in the muscularization of pulmonary arterioles in response to regional hypoxia and in the development of pulmonary arterial hypertension. She has published foundational papers in this area, including her most recent publication in Circulation that is the first to directly implicate Wnt5a in the pathogenesis in pulmonary arterial hypertension, demonstrating that endothelial cells derived from patients with pulmonary hypertension exhibit defective Wnt5a production, resulting in diminished pericyte recruitment; and that Wnt5a-deficient mice exhibit physiologic and histopathologic manifestations of persistent pulmonary hypertension following chronic hypoxia (Yuan et al. Circulation. 2019; 139:1710-1724).
Clinical Trials Program-
Our pulmonary clinical research team remains among the most active clinical trials group in the country, continuing to enroll large numbers of subjects across a diverse set of clinical trials, and continue to serve the Northeastern U.S. and all of New England as a primary referral center for clinical trials in pulmonary disease. The greatest proportion of studies have involved cystic fibrosis. In the past year, we have participated in numerous high-profile Phase III clinical trials examining the efficacy and safety of triple combination CFTR-modulating agents developed by Vertex Pharmaceuticals. We also participated in studies of other CFTR modulators, studies of a new anti-inflammatory drug and led a single site study of the effects of aminoglycosides on hearing. Through all these efforts, of the 92 Clinical Research Centers in the Cystic Fibrosis Therapeutic Development Network (CF-TDN), Boston Children’s Hospital again led the nation as the #1 ranked center for weighted clinical enrollment. We continue to diversify our disease portfolio and will be participating in studies in interstitial lung disease, pulmonary hypertension, and severe asthma. The team is also supporting multiple Division-based translational research efforts, providing personnel, informatics, and regulatory oversight to facilitate patient enrollment, sample collection and processing, and data management. These include gene mapping efforts in Childhood Interstitial Lung Disease (Drs. Alicia Casey and Martha Fishman); several initiatives in the areas of Bronchopulmonary Dysplasia (BPD) and asthma (Drs. Lystra Hayden, Catherine Sheils, and Jonathan Gaffin); and sleep disordered breathing syndromes (Drs. Katwa, Rosen and Katz).
Childhood Interstitial Lung Disease Research-
Building on a strong partnership with the Manton Center and the Division of Medical Genetics, the ChILD group utilizes a pipeline for whole exome sequencing analysis to evaluate undiagnosed cases and continue to grow a local patient registry to facilitate translational research. Early collaboration with the Manton Center has led to the identification of mutations in multiple known and novel genes in separate cases of unexplained diffuse lung disease. BCH is a major contributor of patients to the national chILD registry – a multicenter collaborative developed to accelerate scientific investigation and clinical trials research of these understudied diseases. Through the Pulmonary Biobank and BCH Sequencing Cohort Initiatives, the ChILD team is generating exome sequence data for 200 ChILD patients and their parents for gene discovery purposes.
Bronchopulmonary Dysplasia Research-
Dr. Gaffin’s ongoing work examining the environmental determinants of impaired lung function in children resulted in his award this year of a new R01 from the NIEHS to assess the impact of indoor air quality in both schools and homes on respiratory outcomes in children with BPD. Dr. Hayden continues to make progress on her studies of the early life determinants of obstructive pulmonary disease, continuing to expand the BPD registry at BCH. An analysis of a cohort of former premature infants followed in Pulmonary clinic revealed a worsening obstructive pattern with age, revealing that former premature infants are at risk for ongoing abnormal pulmonary development in childhood. Dr. Sheils has led the implementation protocol of home oximetry which will improve and revolutionize home monitoring of patients with BPD. BCH participated in the PASSIVE study (PrevAlence Study of Severe BPD VEntilation), a multicenter point prevalence study describing ventilation strategies in infants with severe BPD. One of our Division’s second-year fellows is assisting in data analysis for this project.
Sleep-disordered Breathing Research-
Our sleep faculty have made several noteworthy advances this past year. Dr. Umakanth Katwa published an algorithm for management of infants with Pierre Robin sequence. Dr. Dennis Rosen completed a study that identified a much-higher prevalence of periodic limb-movements of sleep in children with Down syndrome than in typical patients. This has resulted in the launching of a joint QI initiative with the Down syndrome program at BCH to improve the screening for and treatment of this condition in children with Down syndrome. This is expected to improve their overall health and to have a positive impact on their ability to integrate into mainstream educational frameworks. Dr. Eliot Katz published two studies on the evaluation and stratification of infants having brief resolved unexplained events.
Medical Education Research- Dr. Debra Boyer
Dr. Boyer is a national leader in pediatric graduate medical education. She has published studies evaluating the balance of service and education in pediatric residency training. She is currently studying upward feedback from pediatric fellows to their attendings with the goal of developing best practices for this process. Additionally, she has developed a curriculum on Fellows as Teachers. Dr. Boyer has also mentored one of our pulmonary fellows in performing a needs assessment of the pediatric pulmonary fellowship curriculum and then developing new teaching initiatives. Finally, Dr. Boyer is involved in studies involving pediatric subspecialty workforce issues.