Role of mTORC1 in ventilator induced lung injury

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DESCRIPTION (provided by applicant): The acute respiratory distress syndrome (ARDS) affects more than 200,000 patients in the US annually and is associated with significant morbidity and mortality rates approaching 40%. The mainstay of supportive treatment for this condition is mechanical ventilation. While frequently life-saving, mechanical ventilation can also exacerbate pre-existing lung injury and cause de novo injury, known as ventilator induced lung injury (VILI). Limiting lung stretch in patients by using low tidal volume ventilation is one of th few strategies that has been shown to decrease mortality in patients with ARDS. Although ventilator management for patients with ARDS has improved, factors such as the regional heterogeneity of the lung injury can lead to persistent injury even with low tidal volume ventilation. To date, no therapies targeted to the specific pathophysiologic mechanisms of lung injury are available for the treatment of patients with ARDS or VILI. Our preliminary data demonstrate that mTOR complex 1 (mTORC1), a multi-protein complex that plays a key role in the regulation of cell growth and response to stress is activated in epithelial cells in a clinicaly relevant murine model combining sepsis from cecal ligation and puncture and VILI with modest tidal volumes (CLP/VILI). Furthermore, we show that mTORC1 activation in CLP/VILI corresponds with impaired autophagy and that pharmacologic mTORC1 inhibition (which increases autophagy) is protective. We hypothesize that mTORC1 activation in lung epithelial cells plays a key role in the development of lung injury in response to mechanical ventilation. To investigate this hypothesis we have proposed the following specific aims: 1) to determine the effects of genetic mTORC1 activation on the development of lung injury in the CLP/VILI model; 2) to determine the effects of pharmacologic mTORC1 inhibition in the CLP/VILI model; 3) to determine the role of stretch induced mTORC1 activation in modulating autophagy and downstream pro-inflammatory pathways in lung epithelial cells. The principal investigator has developed a five-year training program under the guidance of his mentors Drs. Rebecca Baron and Augustine M.K. Choi to develop the skills necessary to become a successful physician- scientist in the field of pulmonary and critical care medicine. The candidate's training will also e overseen by an advisory committee with expertise related to key areas of this proposal including acute lung injury, mTOR biology, and mechanotransduction. The proposed career development plan will provide the additional training necessary to achieve principal investigator's ultimate goal of becoming an independent physician-scientist studying the biologic basis of ARDS and VILI. !