PROJECT SUMMARY Infection-associated acute respiratory distress syndrome (ARDS) is characterized by inflammatory cell infiltration and lung tissue injury, but the mechanism whereby the macrophage interacts with the injured (stiff) matrix to resolve the infection remains poorly understood. This research proposal investigates the role of the mechanosensitive ion channel, Transient receptor potential vanilloid 4 (TRPV4), in integrating the infectious and matrix signals to resolve pneumonia and associated lung injury (ARDS). The long-term goal of our studies is to identify a therapeutic target to enhance resolution of infection-associated ARDS. Our preliminary data show that the TRPV4 signal integrates the matrix and infectious signals through p38 MAPK to enhance macrophage phagocytosis and anti-inflammatory cytokine production. Therefore, we proposed the novel hypothesis: TRPV4 initiated signaling integrates the extracellular matrix stiffness and LPS signals, therefore mediating key elements of the host defense and lung injury response to bacterial pneumonia. This hypothesis will be tested through three interrelated, but independent specific aims: (1) to determine the molecular mechanism whereby TRPV4 signals integrate the extracellular matrix stiffness and LPS signals to enhance macrophage phagocytosis and anti-inflammatory cytokine production; (2) to determine the significance of TRPV4 in a) lung bacterial clearance, b) infection-induced lung injury, and c) lung injury resolution in chronic bacterial pneumonia in mice; and (3) to determine the role of TRPV4 in phagocytosis and anti-inflammatory cytokine production in human macrophages. Our proposal is innovative in concept as it is the first to implicate a matrix stiffness-sensing cation channel (TRPV4) in endotoxin-mediated macrophage phagocytosis. The proposed research is significant as it may discover novel therapeutic targets to treat infection-associated ARDS. This research will be performed in the laboratory of Dr. Olman, Lerner Research Institute (LRI), Cleveland Clinic, and will be advised by experts in immune regulation and lung injury. Along with my mentor, the advisory panel has created a structured career development program, including formal coursework in immunology, cell biology, and translational research. An ideal intellectual and environment is in place at the LRI. My career goal is to build and lead an independent research program that will advance scientific knowledge and patient care in the field of lung injury, repair, and fibrosis. My commitments to research, strong mentorship, dedication of my institution to training the next generation of physician scientists, and environment will allow me to build a career as a physician scientist.