Hermansky-Pudlak Syndrome (HPS) is a family of autosomal recessive disorders characterized by oculocutaneous albinism and highly penetrant pulmonary fibrosis. Despite knowledge of the underlying genetic defects, there are currently no therapeutic or preventative approaches for HPS pulmonary fibrosis. Our published data demonstrate that alveolar epithelial cells (AECs) are the primary drivers of fibrotic susceptibility in HPS; however, the underlying mechanisms by which AECs dysfunction results in fibrosis remain undefined and represent an important knowledge gap in the field of fibrosis research. Studies during the current funding period have enabled us to define key phenotypes of HPS AECs with connections to fibrotic susceptibility in HPS mice. Specifically, we showed excess production of MCP-1 and increased Nox4-mediated ROS production by AECs contributes to fibrosis. A major goal of this proposal is to define how these pro-fibrotic AEC phenotypes relate to the underlying molecular defect in HPS. In search of a mechanism that underlies the observed pro-fibrotic phenotype of AECs in HPS, we recently identified increased TGF? pathway activation in unstimulated HPS AECs. Activated type I and type II TGF? receptors are constitutively recycled into endosomes, and early endosomes have been recognized as a vital signaling organelle for TGF? signaling. Based on our preliminary data, we propose to investigate how compromised endosomal trafficking resulting from the genetic defect in HPS2 (loss of AP-3) alters proteostasis and dysregulates TGF? signaling and AEC function. Our hypothesis is that defective endosomal trafficking in HPS alters TGF? receptor signaling, thereby resulting in persistent and increased Smad and Erk1/2 signaling. These altered signaling pathways result in increased expression of MCP-1, Nox4, and other mediators by AECs that create a pro-fibrotic microenvironment in the distal lung. To test this hypothesis, we propose the following specific aims using cell culture models and a disease relevant HPS mouse model that develops spontaneous and progressive fibrosis with aging: 1) to determine how loss of AP-3 results in increased TGF? signaling and expression of pro-fibrotic mediators by AECs, 2) to determine how AECs promote fibroblast activation in HPS, and 3) to investigate mechanisms of pulmonary fibrosis in HPS that develops with aging. Defining the mechanisms of AEC dysfunction in HPS could provide new insights into pathogenesis of HPS and other forms of pulmonary fibrosis, thus facilitating development of new therapeutic and preventative strategies for this fatal disorder.

Public Health Relevance

Interstitial lung diseases (ILD) are disorders that cause shortness of breath and respiratory compromise due to progressive pulmonary fibrosis. Hermansky-Pudlak Syndrome (HPS) is an inherited disorder in which almost all affected adults develop fatal pulmonary fibrosis. This proposal will use different types of lung cells and HPS mouse models to understand what causes pulmonary fibrosis in HPS and how new therapies might be developed.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Vuga, Louis J
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Children's Hospital of Philadelphia
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