Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung scarring and stiffening, propagated by ?pro-fibrotic? fibroblasts. Recent studies have demonstrated that pro-fibrotic behavior, such as enhanced migration or myofibroblast differentiation, can be driven by the surrounding lung matrix, but the specific biophysical matrix properties, the actual molecular pathway by which these signals are transduced, or its downstream consequences on in vivo fibrosis, have not been fully elucidated. Although the motor protein non- muscle myosin II (NMM2) is known to play a role in generating the cytoskeletal tension required for both fibroblast migration and myofibroblast differentiation in traditional laboratory assays on tissue culture plastic, the role of NMM2 in fibroblast responses to biophysical matrix signals like those encountered in vivo, or NMM2?s role in the pro-fibrotic fibroblast phenotype in IPF, are not known. This research proposal investigates the role of lung matrix signals in driving NMM2-mediated pro-fibrotic fibroblast behavior in IPF. The long-term goal of our studies is to identify a therapeutic strategy to halt fibrogenesis in IPF. Our preliminary data show that 1) the linear matrix fiber organization of normal lung coordinates peripheral activation of NMM2 in fibroblasts to enhance polarized migration, 2) the stiffness of fibrotic lung activates NMM2 centrally in fibroblasts to promote myofibroblast differentiation, and 3) excessive NMM2 activation in IPF fibroblasts leads to a pro-fibrotic phenotype. Therefore, we proposed the novel hypothesis: NMM2 is a key driver of the fibroblast phenotype through its response to biophysical matrix signals. This hypothesis will be tested through three interrelated, but independent specific aims: 1) to determine the biophysical matrix signal by which NMM2 activation drives fibroblast migration and myofibroblast differentiation; 2) to determine the intracellular mechanism by which NMM2 can mediate both migration and myofibroblast differentiation in response to biophysical matrix cues; and 3) to determine the role of NMM2 in pulmonary fibrogenesis in vivo in mice. Our proposal is innovative in concept, as it is the first to implicate NMM2 as a key driver of fibrosis in IPF. The proposed research is significant as it may discover a novel therapeutic approach to halt disease progression in IPF and other fibrotic disorders. The research will be carried out in the laboratory of Dr. Olman at the Cleveland Clinic Lerner Research Institute (LRI), and will be advised by international leaders in the fields of fibrosis, myosin biology, and biomechanical engineering. Along with my mentor, the advisory panel has created a structured career development program, including formal coursework in cell biology and translational research. An ideal intellectual and collaborative environment is in place at the LRI. My career goal is to build and lead an independent research program that would advance scientific knowledge and patient care in the field of IPF. My commitment to research, strong mentorship, and the dedication of my institution to training the next generation of scientific investigators, will allow me to build a successful career as a physician-scientist.

Public Health Relevance

Even with two recently approved treatments in the US, idiopathic pulmonary fibrosis (IPF) continues to be the most rapidly progressive and fatal of all fibrotic conditions. The etiology and underlying biologic mechanisms that promote this precipitous fibrotic cascade are still poorly understood. This project aims to identify how lung tissue matrix drives progressive fibrosis through activation of the motor protein non-muscle myosin II (NMM2) in fibroblasts, which may result in a novel therapeutic strategy of targeting fibroblast-lung matrix interactions in patients with IPF.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
Project #
Application #
Study Section
NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
Program Officer
Kalantari, Roya
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
Zip Code