Role of mTORC1 in ventilator induced lung injury

描述(申请人提供)：急性呼吸窘迫综合征(ARDS)在美国每年影响20多万名患者，与显著的发病率和死亡率相关，接近40%。对这种情况的支持治疗的主要手段是机械通风。机械通气在挽救生命的同时，也会加重原有的肺损伤，引起新的损伤，称为呼吸机诱导的肺损伤(VILI)。通过使用低潮气量呼吸机限制患者的肺伸展是少数已被证明可以降低ARDS患者死亡率的策略之一。虽然ARDS患者的呼吸机管理有所改善，但肺损伤的区域性异质性等因素即使在低潮气量的情况下也会导致持续性损伤。到目前为止，还没有针对肺损伤特定病理生理机制的治疗方法可用于ARDS或VILI患者的治疗。我们的初步数据表明，在调节细胞生长和应激反应中发挥关键作用的多蛋白复合体mTORC1(MTORC1)在临床相关的盲肠结扎穿孔脓毒症和适度潮气量VILI(CLP/VILI)小鼠模型中被激活。此外，我们还表明，CLP/VILI中mTORC1的激活与自噬受损相对应，而药物对mTORC1的抑制(增加自噬)具有保护作用。我们推测，肺上皮细胞中mTORC1的激活在机械通气所致肺损伤的发生发展中起关键作用。为了研究这一假说，我们提出了以下具体目标：1)在CLP/VILI模型中确定mTORC1基因激活在肺损伤发生发展中的作用；2)在CLP/VILI模型中确定药物抑制mTORC1的作用；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Rebecca Baron博士和Augustine M.K.Choi博士的指导下制定了一个为期五年的培训计划，以培养成为肺部和重症监护医学领域成功的内科科学家所需的技能。候选人的培训还将由一个咨询委员会监督，该委员会拥有与这项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，以实现首席研究员的最终目标，即成为一名研究ARDS和VILI生物学基础的独立内科科学家。好了！

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. !