Overarching interests of the laboratory are to define epithelial stem and progenitor cells that maintain the human lung, to define mechanisms that regulate quiescence versus activation of these reparative cells and renewal versus differentiation, in the setting of normal tissue maintenance and lung disease. Our studies benefit tremendously from the participation of patients receiving clinical care for lung disease, who generously provide access to clinical samples that are used to identify candidate cellular and molecular targets for initiation and progression of chronic lung disease. Three-dimensional culture systems and genetically defined animal models are used to define mechanisms of disease and validate therapeutic targets. Areas of research focus include:
Structural Remodeling of the Lung in Chronic Lung Disease
Lung tissue remodeling, suboptimal repair leading to loss of structure and function, is pathognomonic of most chronic lung diseases and accounts for progressive declines in lung function, morbidity and mortality. Chronic diseases of small airways and the gas-exchange region have an enormous societal impact both within the U.S. and worldwide. Of the estimated 225,000 deaths attributed to lung disease in the U.S. in 2007, greater than 50% were due to chronic obstructive pulmonary disease (COPD). Less prevalent but with more limited treatment options is idiopathic pulmonary fibrosis (IPF), the most common type of interstitial pneumonia, which has a mean survival time of three years after initial diagnosis and afflicts upward of 0.2% of the population in North America and Europe.
Our studies seek to define cellular and molecular defects within epithelial cells that lead to repair defects and scar formation, and modeling of these events using 3D culture systems and through genetic manipulation in mice. Data below highlight advanced genomics approaches that are being used to define pathways that are defective in epithelial stem cells of the IPF lung and mouse models that are being employed to investigate mechanisms of disease.
Our studies seek to establish preclinical mouse models of COPD to understand basic mechanisms that drive initiation and progression of disease and for validation of candidate therapies.
Cystic fibrosis is a monogenic disorder affecting approximately 1 in 2500 births or an estimated 70,000 individuals worldwide. The underlying genetic defect involves mutations that impact functionality of the cystic fibrosis transmembrane conductance regulator (CFTR), leading to defects in electrolyte transport. The most pronounced clinical manifestations of cystic fibrosis result either from epithelial dysfunction and mucus plugging in many different tissues including the upper and lower respiratory tract, gastrointestinal tract and reproductive tract, or from defects in nutrient and salt absorption/secretion. The advent of novel pharmacologic approaches to modulate CFTR trafficking or function has provided effective therapeutic options for approximately 75% of patients. However, improved options that go beyond palliative therapy are desperately needed for the thousands of patients that are not responsive to CFTR modulator therapy. Our goals are to provide an improved understanding of epithelial defects observed in lungs of patients with CF lung disease and to develop stem cell replacement therapies aimed at providing treatment options to patients that are not responsive to current drug therapies.
Lung cancer remains the leading cause of cancer-related deaths both nationally and worldwide. Of lung cancer cases, non-small cell lung cancers (NSCLC) are the most prevalent with adenocarcinoma (ADC) and squamous cell carcinoma (SCC) accounting for 85% of all NSCLC cases. Adenocarcinomas include a rage of overlapping sub-histotypes that collectively represent the most common subtype of NSCLC. A pervasive problem in the treatment of all cancers is their ability to undergo somatic mutations leading to the generation of a heterogeneous population of tumor cells, each of which has the potential to show unique profiles of sensitivity to commonly used chemotherapeutic drugs.
Our studies seek to define tumor cell heterogeneity within patient-derived primary lung adenocarcinoma samples through use of state-of-the-art technologies for single cell molecular profiling and to use in vitro 3D cultures for disease modeling.
Acute Lung Injury
Lung tissue remodeling following acute respiratory viral infection
Basal cell (BC) hyperplasia is a common pathological feature of chronic lung disease and acute H1N1 influenza virus infection. However, the cell types that contribute to their formation and impact of surrounding microenvironmental cues that influence the behavior of BCs have yet to be fully elucidated.
To address this knowledge gap, we have employed single cell transcriptomics and dual recombinase fate-mapping in mice to assess dynamic changes in the molecular landscape and fate of lung epithelium following influenza infection. Our studies define a rare subpopulation of intralobar serous cells as a progenitor cell-of-origin for nascent BC that expand in airways and repopulate the injured gas-exchange region following viral infection. Additionally, we show that the balance between BC renewal versus differentiation into serous-like cells is influenced by innate immune activation and local production of IL-22. In summary, our data show that preexisting intralobar serous cells are a major source of expanding BCs in lungs of influenza virus-infected mice, while their subsequent differentiation back into serous cells is blocked by increased local production of IL-22.