VENTILATOR ASSOCIATED LUNG INJURY: MOLECULAR APPROACHES

描述(申请人提供)：急性肺损伤(ALL)是一种在脓毒症和其他全身性炎症障碍的背景下发生的破坏性疾病，机械通气介导的应激对患者的不利结局有明显的贡献。这项SCCOR应用侧重于了解ALL患者中机械通气与发病率和死亡率增加之间的复杂相互作用。随着人类基因组图谱的绘制，高通量技术现在为有意义的转译研究提供了潜力，以解决(I)合理机械通气策略的分子基础，以及(Ii)机械应激与遗传易感患者病理基因表达激活的关系。由于ALL和呼吸机相关ALL(VALI)可能是异质分子过程的表现，这是SCCOR应用的主题基础，基因组技术的进步不仅提供了机会，以提高敏感性和清晰度来表征肺对VALI的反应，而且还为潜在的治疗确定新的分子靶点。我们建议对急性肺损伤的人类和动物模型进行全面的基因组和蛋白质组研究(具有严格的表型特征)，并在大量表型良好的ALL患者中表征潜在的重要多态。重要的是，这些研究将得到创新研究的补充，这些研究旨在评估替代的所有呼吸策略，并测试针对VALI介导的肺水肿形成的新疗法。霍普金斯SCCOR应用程序代表了一个具有多学科专业知识的研究人员联盟，其共同目标是将基础研究发现转化为ALL患者的直接利益。在六个高度互动的核心(管理、数据管理和分析、分子病理学、犬类模型核心、基因组/基因分型和生物标记物/蛋白质)的支持下，六个人类和动物项目将利用最先进的分子方法和新的表型 该仪器不仅可能对VALI迄今的关键病理生物学过程提供最深入的了解，而且还将确定与急性肺损伤相关的关键遗传决定因素。我们预计，我们的工作将促进新策略的开发，发现新的治疗靶点，并定义新的预后指标，以限制机械通气对急性损伤肺的不良影响。

DESCRIPTION (provided by applicant): Acute lung injury (ALl) is a devastating illness occurring in the context of sepsis and other systemic inflammatory disorders with a clear contribution of mechanical ventilation-mediated stress to adverse patient outcomes. This SCCOR application is focused on understanding the complex interplay between mechanical ventilation and the increased morbidity and mortality noted in patients with ALl. In concert with the mapping of the Human Genome, high throughput technologies now provide the potential for meaningful translational research to address (i) the molecular basis for rational mechanical ventilation strategies, and (ii) the relationship of mechanical stress to the activation of pathological gene expression in genetically-susceptible patients. Because ALl and ventilator-associated ALl (VALI) are likely manifestations of heterogeneous molecular processes, it is a thematic underpinning of this SCCOR application that advances in genomic technology provide the opportunity to not only characterize pulmonary responses to VALI with increased sensitivity and clarity, but to also identify new molecular targets for potential therapy. We propose to conduct comprehensive genomic and proteomic studies of human and animal models of acute lung injury (with rigorous phenotypic characterization) and characterize potentially important polymorphisms in a large cohort of well-phenotyped patients with ALl. Importantly, these studies will be complemented by innovative studies designed to assess alternate ALl ventilatory strategies and to test novel therapies for VALI-mediated lung edema formation. The Hopkins SCCOR application represents a consortium of investigators with multidisciplinary expertise, and the common goal to translate basic research discoveries into direct benefit for patients with ALl. Supported by six highly interactive cores (Administration, Data Management and Analysis, Molecular Pathology, Canine Models Core, Genomic/Genotyping, and Biomarkers/ Proteomic), the six human and animal projects will utilize state-of-the-art molecular approaches with novel phenotyping instrumentation that will not only likely provide the deepest understanding of critical pathobiologic processes in VALI to date, but define key genetic determinants relevant to acute lung injury. We anticipate our work will facilitate development of new strategies, uncover new therapeutic targets and define new prognostic indicators that will limit the adverse effects of mechanical ventilation on the acutely injured lung.