Macropinocytosis and Pulmonary Fibrosis

PROJECT SUMMARY/ABSTRACT This R01 proposal describes a five-year research plan that will facilitate a research program dedicated to determining the roles of macropinocytosis and its molecular mechanisms in pulmonary fibrosis. Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, fibroproliferative interstitial lung disease whose etiology remains unknown. Little is known about the molecular mechanisms involved in the pathogenesis of IPF. This project will focus on elucidating the key roles of macropinocytosis in lung fibrogenesis, as well as their therapeutic applications. Macropinocytosis is an actin-dependent but clathrin-independent endocytic process that mediates the nonselective internalization of extracellular contents, such as proteins and free amino acids (AA). Macropinocytosis is one of the major routes of nutrient uptake from the extracellular environment for various cells and is known to be involved in cell survival, migration, and metabolism. However, the role of this process in lung fibrogenesis is currently unknown. Our preliminary findings suggest that the inhibition of macropinocytosis attenuates myofibroblast differentiation and lung fibrosis in mice. Here, we will determine whether macropinocytosis exerts profibrotic responses in lung fibroblasts and experimental pulmonary fibrosis. Further, we will also identify the molecular mechanisms by which macropinocytosis regulates profibrotic responses in activated lung fibroblasts. We will test our hypotheses by addressing the following Specific Aims: In Aim 1, we will assess whether macropinocytosis deficiency attenuates fibrosis in repetitive and aged models of pulmonary fibrosis, primary cell culture system and precision cut lung slices. In Aim 2, we will determine the effect of macropinocytosis-mediated amino acid uptake on the expression of profibrotic genes in activated lung fibroblasts. In Aim 3, we will assess the potential anti-fibrotic effect of macropinocytosis inhibitors in pulmonary fibrosis.