Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease that compromises gas exchange in the alveoli. The median survival following diagnosis is approximately 3 years and there are few effective therapies. Although the specific causes of IPF are unknown, inhalation of dust, cigarette smoke and toxic chemicals are known risk factors for developing the disease, which most commonly develops in males as they enter their 60s and 70s. In view of these risk factors, the Department of Veterans Affairs has become increasingly concerned about the potential for previously deployed US Veterans to develop IPF. One of the cardinal features of IPF is the accumulation and persistence of fibroblasts in the alveoli and alveolar septa. Fibroblasts participating in homeostatic repair processes undergo apoptosis at the completion of the repair process. In contrast, fibroblasts from the lungs of IPF patients are resistant to apoptosis. Our lab has had a long-standing interest in fibroblast apoptosis and the role of the death receptor Fas in this process. This proposal is focused on the mechanisms that cause the resistance of lung fibroblasts from IPF patients to apoptosis. In preliminary studies, we have identified the protein tyrosine phosphatase, PTPN13 (also called PTP-BL in mice), as a central mediator of the resistance of human lung fibroblasts to Fas-induced apoptosis. PTPN13 inhibits apoptosis by binding to the C-terminal cytoplasmic region of Fas, thereby preventing recruitment of the required death signaling molecules FADD and caspase-8. Our preliminary studies suggest that PTPN13 is a therapeutic target, which, when antagonized, will overcome the resistance of fibrotic lung fibroblasts to Fas-induced apoptosis. We hypothesize that interfering with PTPN13 function will restore the ability of fibrotic lung fibroblasts to undergo Fas-induced apoptosis, leading to a progressive reduction in lung fibroblast numbers a resolution of established fibrosis. This hypothesis will be tested with 3 specific aims.
In aim 1, we propose investigating the consequence of genetic deficiency of PTP-BL (the murine orthologue of human PTPN13) on resolving and non-resolving models of pulmonary fibrosis in mice. Using specific analytic methods developed for this proposal, including fibroblast lineage tracing, we propose investigating the effect of PTP-BL deficiency on lung fibroblast numbers and fibrosis resolution. Next, while genetic deficiency of PTP-BL is a useful experimental tool, our goal is to rapidly translate our work into humans. Consequently we have developed a therapeutic pipeline to identify small molecule inhibitors of the interaction between Fas and PTPN13. Using a high throughput assay to screen 20,831 small molecules and FDA-approved drugs, we have identified 3 molecules that behave as mimetics of the Fas sequence responsible for its interaction with PTPN13. These small molecules competitively inhibit the interaction between Fas and PTPN13 and sensitize lung fibroblasts to Fas-induced apoptosis. Furthermore, one of the molecules is an FDA-approved drug, shortening the pipeline for therapeutic development.
In aim 2, we propose testing this drug for its ability to enable fibroblas apoptosis in a humanized mouse model and resolve established pulmonary fibrosis. Lastly, in aim 3 we proposed investigating the mechanisms controlling PTPN13 expression. Our preliminary studies suggest that lung stiffness is an important factor in this event. Collectivel, the proposed studies should innovative understanding of fibroblast persistence in pulmonary fibrosis, address a novel therapeutic target (PTPN13) and provide proof-of-concept data about a repurposed FDA-approved drug that by antagonizing PTPN13 function is predicted to augment lung fibroblast apoptosis and resolve established pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a fatal, aging-associated fibrotic lung disease resulting in the premature deaths of 43,000 Americans per year. With reduced quality of life, a median survival of 2-3 years following diagnosis and a paucity of effective therapies, the outlook for IPF patients is undeniably bleak. Cigarette smoking and environmental dust exposure, both common among deployed US military personnel and Veterans, constitute established risk factors for disease development. Additionally, the Department of Veterans Affairs has predicted that deployed military persons exposed to burn pits, pollutants and sand may have an increased risk of developing IPF. Thus, there remains an urgent need to: (i) understand the mechanisms that control the development of fibrosis in IPF patients and (ii) develop mechanism-based innovative therapies. Therefore, the development of mechanistic studies and innovative therapies to treat IPF patients is of substantial relevance to improving veterans' healthcare, as well as that of the general population.
| Bamberg, Alison; Redente, Elizabeth F; Groshong, Steve D et al. (2018) Protein Tyrosine Phosphatase-N13 Promotes Myofibroblast Resistance to Apoptosis in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 198:914-927 |
