The pathogenesis of interstitial lung disease (ILD) is largely unknown, and existing treatments are of limited benefit in alleviating the associated high morbidity and mortality. Abnormalities in alveolar type II cell function are commonly implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), and are central features of ILD associated with mutations in surfactant protein C (SP-C) and the ATP-binding cassette A3 (ABCA-3). Monogenic disorders of lung fibrosis provide a unique opportunity to study fibrogenesis from the vantage point of a primary molecular defect. Hermansky-Pudlak Syndrome (HPS) is an autosomal recessive disorder of organellogenesis, characterized by albinism, platelet dysfunction, and highly penetrant and frequently fatal pulmonary fibrosis in the fourth or fifth decade of life. We have found that the naturally occurring Pearl mouse model of HPS, which has a mutation in the adaptor protein 3 (AP-3) complex required for organelle biogenesis and protein trafficking, has a phenotype that mimics the human condition.
The Aims of this proposal are: (1) To determine the mechanisms of dysregulated pulmonary inflammation in Pearl HPS mice, and (2) To determine the mechanisms of fibrotic susceptibility in Pearl HPS mice.
Both aims will employ genetic and cellular replacement, with type II cell-specific transgenesis and murine bone marrow transplantation, to define the contributions of alveolar macrophages and alveolar type II cells to the pulmonary phenotype of the Pearl mouse. Our long term objective is to use cellular and molecular insights into alveolar homeostasis and the pathogenesis of HPS lung disease to enhance the understanding and therapeutic approach to more common fibrotic lung disorders. The candidate trained in both pediatric and adult pulmonary medicine and is an Instructor of Pediatrics and Medicine. Her research mentor is Dr. Francis X. McCormack. In order to facilitate her goal of becoming an independent basic investigator with an emphasis on mechanisms of pulmonary fibrosis and genetic lung disease, the proposed training plan includes a combination of didactic coursework and mentoring that draws on the expertise in pulmonary biology that exists in Cincinnati. Simply put, this proposal will use a powerful genetic mouse model to understand how scarring occurs in the lung, and how scarring in the lung might be prevented.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1-CSR-O (F1))
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Colombini-Hatch, Sandra
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Vanderbilt University Medical Center
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United States
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