Grant: CIHR REDI Early Career Transition Award - Infectious Disease and Immune System

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease where the lungs become progressively scarred (or fibrotic), making it difficult to breath and supply oxygen to the body. Patients diagnosed with IPF will die within three to five years, and available treatments only modestly slow disease progression. Given the poor prognosis for individuals diagnosed with IPF, it is imperative to determine what causes the progressive lung scarring characteristic of this disease and how to stop this process once it has begun. Research has revealed that the scarring process in IPF is associated with two major changes in the lung: the hyperactivation of inflammatory responses, and increased deposition and stiffening of extracellular matrix (ECM) that surrounds cells. Importantly, recent studies indicate that cells are strongly affected by the composition and stiffness of ECM, and this can lead to changes in cell behavior and function in a process termed mechanosignaling. Importantly, my preliminary studies suggest that ECM stiffness triggers mechanosignaling in lung cells, and this facilitates the activation of inflammatory responses. These observations suggest that the stiff ECM in scarred lung tissue may be a driver of inflammatory responses in IPF. Therefore, I will use a combination of advanced biochemical, bioengineering and biophysical approaches, to unravel how mechanosignaling in response to stiff ECM promotes inflammation within lung tissue. Insights into the role of stiff, fibrotic ECM in aberrant mechanosignaling and inflammation will illuminate novel mechanisms that contribute to IPF and pathways that may be targeted to alleviate disease. Tissue fibrosis is a hallmark of many age-related diseases, including cardiovascular disease and cancer. Thus, my work may have broader utility for the understanding and treatment of other age-related fibrotic diseases.