Sunday, May 5, 2024
5/5/2024
PROJECT SUMMARY Idiopathic pulmonary fibrosis (IPF) is a chronic age-associated disease with a median survival of 3-5 years following diagnosis. Current antifibrotic treatments, pirfenidone and nintedanib, slow the progression of IPF but are insufficient in halting or reversing this disease. While the etiology remains unknown, fibroblast-mediated extracellular matrix (ECM) remodeling leading to the development of fibroblastic foci appears to be a critical component of IPF. The objective of this project is to engineer an in vitro 3D pulmonary microtissue model to explore the contribution of age-associated pathways to fibroblast-mediated ECM remodeling. My previous work generating microtissues supports the feasibility of developing this in vitro 3D pulmonary microtissue model. Additionally, microtissues have been previously used to study cell-matrix interactions including in the context of fibrosis. A main advantage of using the microtissues system to study fibrotic diseases is the ability to assess real-time changes in contractility and cell migration in a medium throughput system. My central hypothesis is that senescence-associated secretory phenotype (SASP) and the development of an apoptosis-resistant phenotype in senescent fibroblasts contribute to ECM remodeling in IPF. The overall objective and hypothesis will be accomplished across three specific aims: 1) Engineer pulmonary microtissues using human fibroblasts isolated from IPF and healthy tissues of various ages; 2) Evaluate the senescence-associated secretory phenotype of IPF fibroblasts and determine its effects on microtissue remodeling; and 3) Assess the development of an apoptosis-resistant phenotype in senescent cells and evaluate the role of FAK in regulating apoptosis. Expected outcomes for this project include: 1) An in vitro pulmonary microtissue model capable of detecting differences in microtissue contractility, stiffness, cell migration, and ECM remodeling; 2) Determining the impacts of SASP on ECM remodeling and evaluating the therapeutic benefit of targeting specific components of SASP; and 3) Assessing FAK’s role in preventing apoptosis in senescent cells and evaluate the therapeutic benefit of FAK inhibition. The results of this study will elucidate the role of fibroblast senescence in the development and progression of pulmonary fibrosis and identify potential druggable targets.
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