Targeting Membrane Repair in Deformation-Induced Lung Injury

描述(申请人提供)：呼吸机相关性肺损伤(VALI)的中心病理生理学是在机械通气过程中，当肺膨胀超过其正常潮气量时，肺上皮细胞的动态撕裂和修复。我们以前已经证明，肺泡细胞损伤在VALI症状的发展中起着重要作用。然而，修复肺泡细胞损伤的分子成分仍然是完全神秘的。我们的研究小组之前的工作在横纹肌中发现了Mitsugumin 53(MG53)，它感知膜破裂部位氧化状态的变化，并穿梭于预先组装的膜相关小泡来修补骨骼肌细胞的质膜断裂。我们的初步研究发现，MG53在肺细胞中表达，MG53-/-肺对VALI易感。在本研究中，我们旨在确定肺泡细胞修复的分子成分以及MG53在VALI中的作用。该项目的总体目标是更好地了解MG53介导的膜修复在VALI中的作用，并开发一种基于重组蛋白的治疗VALI的方法。本项目的具体目的是：1)确定MG53介导的膜修复在肺上皮细胞膜损伤中的保护作用；2)确定MG53在VALI发生发展中的体内功能；3)探讨重组MG53蛋白治疗VALI的可能性。这些研究为确定MG53是否是变形诱导的肺上皮细胞损伤修复的中心分子，以及MG53介导的细胞膜修复的调节是否为治疗VALI的潜在有效手段提供了直接的测试。此外，我们的研究结果将推动推动一种安全有效的治疗方法 参与蛋白质大规模生产的VALI自然存在于人体内。

DESCRIPTION (provided by applicant): The central pathophysiology of ventilator-associated lung injury (VALI) is dynamic tearing and repairing of the lung epithelial cells during mechanical ventilation when the lung is inflated beyond its normal tidal volume. We have shown previously that wounding of alveolar cells plays an important role in the development of VALI symptoms. However, the molecular components to repair alveolar cell injury remain completely mysterious. Previous efforts of our research team identified Mitsugumin 53 (MG53) in striated muscle, which senses changes in oxidative status at the membrane disruption site and shuttles pre-assembled membrane-associated vesicles to patch plasma membrane breakage in skeletal muscle cells. Our pilot study has found that MG53 expresses in lung cells and mg53-/- lung is susceptible to VALI. In this study, we aim to identify the molecular component for the repair of alveolar cells and the contribution of MG53 in VALI. The overall goal of this project is to gain a greater understanding for the role of MG53-mediated membrane repair in VALI and to develop a recombinant protein-based therapy for the treatment of VALI. The specific aims of this project are: 1) to establish the role of MG53-mediated membrane repair in protection against membrane injury to lung epithelial cells in culture, 2) to determine the in vivo function of MG53 in the development of VALI, and 3) to explore the potential of using recombinant MG53 protein for the treatment of VALI. These studies represent a direct test to determine if MG53 is a central molecule for repair of deformation-induced injury to lung epithelial cells, and whether modulation of MG53-mediated cell membrane repair represents a potential effective mean for the treatment of VALI. In addition, our results will push the efforts for advancing a safe and potent therapy for VALI that involves in large-scale production of a protein naturally exists in the human body.