Syndecan-1 regulation of lung fibrosis

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ABSTRACT This proposal is for the career development of Tanyalak Parimon, M.D., into an independent physician-scientist focused on basic/translational research in lung fibrosis. The PI will have as co-mentors Peter Chen, M.D., who has an established research program in the lung biology of syndecan-1 and Dolores Di Vizio, M.D., Ph.D., who is a leading expert in extracellular vesicle biology. The comprehensive training program will include laboratory- based research, didactic lectures, coursework and workshop, grantsmanship, scientific conferences (internal and external), and career guidance by a scientific advisory committee that includes the co-mentors. With this proposal, I will have the opportunity to continue to learn and broaden my research skills and knowledge of mechanisms of lung injury and repair with a focus in lung fibrosis and extracellular vesicle (EVs) biology. Additionally, I will leverage the scientific and technical knowledge of leading respiratory research and EVs experts at Cedars-Sinai and the greater Los Angeles area in performing my research and in my training to become an independent physician-scientist. For the research proposal, I will be furthering our understanding into mechanisms of lung fibrosis pathogenesis with the long-term goal to identify the cellular target(s) for a novel therapeutic option for lung fibrosis and to become a leading independent investigator in this field. Syndecan-1, a transmembrane heparan sulfate proteoglycan primarily expressed on epithelial cells, has extensive roles in epithelial cells injury and repair, and I show that it has a central role in lung fibroproliferative diseases. The mechanism that I will explore and is supported by my preliminary data is that syndecan-1 altered the miRNA profile within extracellular vesicles (EVs) secreted by the alveolar epithelial type II cells (AECII) to promote fibrogenic changes within the lung microenvironment. These findings led to the hypothesis that syndecan-1 promotes lung fibrosis by controlling anti-fibrotic miRNAs packaging in EVs, thereby reshaping the lung microenvironment to promote fibroproliferation. Under this career development award, I propose to test the hypothesis with three specific aims: 1) Identify mechanisms by which syndecan-1 regulates miRNA packaging into EVs; 2) Elucidate how syndecan-1 facilitates fibrosis by promoting AECII senescence; and 3) Evaluate how syndecan-1 controls fibrotic epithelial-derived EVs to augment fibroproliferation.