My lab uses genetic and genomic techniques to determine the molecular basis of various adult pulmonary diseases. The lungs are complex structures that provide effective exchange of inhaled oxygen for exhaled carbon dioxide. This interface is located in the distal lung and includes alveolar surfactant, the alveolar epithelial cells, and the supporting interstitium in which the capillary vascular bed resides. Diseases of the pulmonary system can affect the delicate balance of cells and proteins within the distal lung.
Using large kindreds with familial pulmonary disease, we have used genetic linkage and sequencing of candidate genes to find rare mutations in various genes.
The inherited form of pulmonary fibrosis, a scarring disease of the distal lung that affects adults, can be caused by mutations in genes belonging to two major pathways.
Germline loss-of-function mutations in the genes encoding telomerase (TERT or TERC) are found most frequently in the familial form of the disease. This subset of patients and families has a “telomeropathy” that is characterized by short telomere lengths.
The second known major pathway affected in familial pulmonary fibrosis is the surfactant pathway. The phospholipids and proteins in surfactant are secreted by the type II alveolar epithelial cells. Mutations in the genes encoding surfactant protein C (SP-C) and, more recently, surfactant protein A2 (SP-A2) are associated with familial pulmonary fibrosis.
Recombinant mutant proteins demonstrate protein instability and lead to increased ER stress. Human alveolar wash samples from individuals heterozygous for the SP-A2 mutation have normal levels of total SP-A which suggests that the mechanism of disease does not involve an overt lack of secreted SP-A, but instead an increase in ER stress of type II alveolar cells.