Wednesday, May 8, 2024
5/8/2024
PROJECT SUMMARY Pulmonary fibrosis is a class of disease conditions characterized by subacute and chronic progressive scarring of the lungs. The most common form, idiopathic pulmonary fibrosis (IPF), has a prevalence of 1 in 200 among people older than 65. IPF is a devastating disease with a median survival of 3 to 5 years with limited therapy to halt its progression. Recent research had highlighted the critical role of macrophages, particularly monocyte- derived macrophages (MDMs), in pulmonary fibrosis. Macrophages are highly plastic and undergo metabolic reprogramming and alternative activation during fibrosis. The interactions of macrophages and their fibrotic environment are crucial for fibrosis progression. Numerous studies have shown that different biochemical signals can induce macrophage metabolic reprogramming and alternative activation; however, limited data are available to demonstrate whether physical signals such as enhanced extracellular matrix (ECM) stiffness, the cardinal changes during lung fibrosis, can modulate macrophage metabolic reprogramming and alternative activation. Our preliminary data showed that macrophages cultured on matrix with stiffness similar to fibrotic lungs (20 kPa) had increased PPAR¿ compared to macrophages cultured on a soft and compliant matrix with stiffness similar to normal health lungs (0.5 kPa). Integrin ß3 is increased in lung macrophages from human subjects with pulmonary fibrosis and animal with experimental fibrosis. Mechanistically, we hypothesize that macrophages utilize integrin ß3 as the mechanosensor to activate PPAR¿ to modulate metabolic reprogramming and alternative activation. In Aim 1, we will determine if ECM-stiffness regulates macrophage metabolic reprogramming. In Aim 2, we will determine the mechanosignaling pathway utilized by macrophages to modulate metabolic reprogramming. In Aim 3, we will test our hypothesis in an experimental pulmonary fibrosis mice model to determine whether interrupting PPAR¿-mediated mechanosignaling and metabolic reprogramming in macrophages can attenuate pulmonary fibrosis in vivo. By completing this proposed study, we aim to show that 1) macrophages sense ECM stiffness via Integrin avß3; 2) matrix stiffness can modulate macrophage metabolism to sustain its alternative activation; 3) PPAR¿ is a mechanosensitive transcription factor, and 4) inhibiting avß3-PPAR¿ mechanotransduction pathway in macrophages can attenuate pulmonary fibrosis in vivo. I will utilize this proposal to acquire additional skills in the cutting-edge field of mechano- immuno-metabolomics through a series of didactic and applied training under the mentorship of an experienced multidisciplinary team. This K08 will facilitate my transition to an independent physician-scientist studying the pathogenesis of pulmonary fibrosis, with a unique research niche of mechano-immuno- metabolomics. This research proposal will also aid in identifying novel mechanisms and targets for therapies in pulmonary fibrosis, which is fatal and with limited treatment.
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