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The Children's Research Institute

Airway and Lung

Pleuropulmonary blastoma

Pleuropulmonary blastoma (PPB) is a rare lung sarcoma that affects children under six years of age. PPB is a prominent feature in a recently described tumor predisposition syndrome in which family members are also at increased risk for developing other organ-based childhood cancers including rhabdomyosarcoma, ovarian Sertoli-Leydig tumors, neuroblastoma, medulloblastoma, and kidney and eye tumors. Ashley Hill, MD, is an international authority on PPB, having identified the first mutations underlying this disease (a unique microRNA mechanism).

Faculty with interests in pleuropulmonary blastoma (PPB) include:

Mucous and airway disease

The overproduction of mucus and mucins in the upper and lower respiratory tracts contributes to the morbidity and/or mortality rates of pediatric airway diseases, including asthma, cystic fibrosis (CF), chronic rhinosinusitis (CRS), and otitis media (OM). Dr. Mary Rose’s research on down-regulation of secretory mucin genes by dexamethasone (classical glucocorticoid) and VBP15 (dissociative glucocorticoid) has shown that repression by dexamethasone is transcriptional and mediated by the glucocorticoid receptor and histone deacetylase 2.

Mucus/mucin hypersecretion in the sinus mucosa is driven by submucosal gland hyperplasia. The question of how mediators triggered by inflammation or cigarette smoke activate the mechanisms that lead to glandular hyperplasia and mucin gene upregulation are being addressed by Maria Pena, MD, Diego Preciado, MD, Xiaofang Wu, MD, MPharm, and Mary Rose, MD, using three types of in vitro models that were recently developed. Mucin hypersecretion also contributes to the pathology of otitis media (OM) in children. Dr. Preciado is investigating the mechanisms that lead to OM and upregulation of MUC5B (major mucin in chronic OM effusion) in a newly-funded R01 grant using expression array and proteomic approaches to look at the effect of cytokines, bacterial products, and tobacco smoke on middle ear epithelial cells in vitro and in vivo.

Proteomic analyses are being carried out on differentiated human bronchial epithelium from asthmatic and CF cells, as well as on bronchial casts (from patients with sickle cell disease, congenital ear disease, and respiratory disorders), and lung mucus from patients with Hyper IgE syndrome. Secretome data will be used to interrogate and compare lung mucosal components from pulmonary patients to elucidate the underlying pathophysiology of mucus hypersecretion in these diseases, with the hope of ultimately targeting treatment options and improving patient outcomes.

Faculty with interests in mucous and airway disease:

Lung-related diseases

Lung-related research at Children's Research Institute continues to increase. Robert Freishtat, MD, leads efforts on behalf of NIH-funded multicenter studies of genetic changes in overwhelming infections (sepsis) in children. Additionally, he is developing a new treatment for the complications of sepsis targeting a blood platelet protein, together with Matthew Sharron, MD. The efforts of Juan Ibla, MD, are focused on understanding the impact of environmental hypoxia on pulmonary epithelial cell cycle and dyssynchronous tissue remodeling. Linda Leatherbury, MD, and Iman Sami-Zakhari, MD, in collaboration with Dr. Cecilia Wu’s group at the University of Pittsburgh, have shown that congenital heart disease patients with heterotaxy have a substantial risk for ciliary dyskinesia and increased respiratory disease and are enriched in mutations in primary ciliary dyskinesia genes. This work is now being expanded to examine ciliary function in other conditions that encompass chronic lung disease.

Dr. Colberg-Poley’s group studies how human cytomegalovirus (HCMV), a lung pathogen, reprograms cellular metabolism. HCMV infection targets mitochondria-associated membranes (MAM), an endoplasmic reticulum (ER) subdomain that contacts mitochondria. The MAM provides sites for calcium (Ca2+) signaling to mitochondria (required for cellular metabolism), senses and responds to ER stress, coordinates mitochondrial antiviral signaling, and induces mitochondrial-mediated programmed cell death. Her group found that an HCMV protein (pUL37x1) traffics through the ER, MAM, and to mitochondria. Further, her group found that pUL37x1 recruits the proapoptotic protein Bax to the MAM and targets it for proteasomal mediated degradation. In collaboration with Drs. Yetrib Hathout and Kristy Brown, her group performed quantitative proteomic analyses on the MAM in normal human fibroblasts and at late times of HCMV infection. The studies generated the first global definition of human MAM proteome and found that HCMV dramatically changes the MAM proteome.

Dr. Geovanny Perez, a pulmonary fellow, has joined Dr. Colberg-Poley’s group to define the microbiome of patients with cystic fibrosis using next generation sequencing. Diagnosing bacterial respiratory pathogens particularly in patients with chronic lung diseases is challenging. The lung microbiome is complex and dynamic. As most bacteria will not grow under standard conditions, culture conditions of lung microbiome in cystic fibrosis patients required special (anaerobic) conditions and extended incubation times. Recently, next generation sequencing has been successfully used to identify bacteria in the lung microbiome of patients with chronic obstructive pulmonary disease (COPD). In collaboration with Eric Hoffman, PhD, Joseph Devaney, PhD, and Dinesh Pillai, MD, Dr. Colberg-Poley will use next generation sequencing to determine microbial populations in bronchiolar lavages from cystic fibrosis patients.

Faculty with interests in lung-related disease include: