Role of mTORC1 in ventilator induced lung injury

描述（由申请人提供）：在美国，急性呼吸窘迫综合征（ARDS）每年影响超过20万患者，其发病率和死亡率接近40%。这种情况的主要支持治疗是机械通气。机械通气虽然经常挽救生命，但也会加重已有的肺损伤并引起新生损伤，即呼吸机性肺损伤（VILI）。通过使用低潮气量通气来限制患者的肺伸展是已被证明可以降低ARDS患者死亡率的少数策略之一。尽管ARDS患者的呼吸机管理已经得到改善，但肺损伤的区域异质性等因素可能导致即使采用低潮气量通气也会造成持续性损伤。迄今为止，还没有针对肺损伤特定病理生理机制的治疗方法可用于治疗ARDS或VILI患者。我们的初步数据表明，mTOR复合物1 （mTORC1）是一种多蛋白复合物，在细胞生长和应激反应的调节中起关键作用，在临床相关的小鼠模型中，由盲肠结扎和穿刺引起的脓毒症和具有适度潮气量（CLP/VILI）的VILI在上皮细胞中被激活。此外，我们发现CLP/VILI中的mTORC1激活与自噬受损相对应，药理学上的mTORC1抑制（增加自噬）具有保护作用。我们假设肺上皮细胞中的mTORC1激活在机械通气肺损伤的发展中起关键作用。为了验证这一假设，我们提出了以下具体目标：1)确定遗传mTORC1激活对CLP/VILI模型肺损伤发展的影响；2)确定药物抑制mTORC1对CLP/VILI模型的影响；3)确定拉伸诱导的mTORC1激活在调节肺上皮细胞自噬和下游促炎通路中的作用。首席研究员在他的导师博士的指导下制定了一个为期五年的培训计划。丽贝卡巴伦和奥古斯丁M.K.崔发展必要的技能，成为一个成功的医生-科学家在肺和重症医学领域。候选人的培训也将由咨询委员会监督，该委员会具有与本提案的关键领域相关的专业知识，包括急性肺损伤、mTOR生物学和机械转导。拟议的职业发展计划将提供必要的额外培训，以实现首席研究员成为研究ARDS和VILI生物学基础的独立内科科学家的最终目标。！

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. !