VENTILATOR ASSOCIATED LUNG INJURY: MOLECULAR APPROACHES

描述（由申请人提供）：急性肺损伤（AL 1）是一种在败血症和其他全身性炎症性疾病背景下发生的毁灭性疾病，机械通气介导的应激对不良患者结局有明显影响。 该SCCOR应用集中于理解机械通气与在ALL患者中注意到的发病率和死亡率增加之间的复杂相互作用。 与人类基因组图谱相一致，高通量技术现在为有意义的转化研究提供了潜力，以解决（i）合理机械通气策略的分子基础，以及（ii）遗传易感患者中机械应力与病理基因表达激活的关系。 因为AL 1和呼吸机相关AL 1（VALI）可能是异质分子过程的表现，所以该SCCOR应用的主题基础是基因组技术的进步提供了不仅以增加的灵敏度和清晰度表征对VALI的肺响应，而且还鉴定用于潜在治疗的新分子靶标的机会。 我们建议对急性肺损伤的人类和动物模型（具有严格的表型表征）进行全面的基因组和蛋白质组学研究，并表征具有ALL的良好表型患者的大队列中潜在重要的多态性。 重要的是，这些研究将通过创新性研究进行补充，这些创新性研究旨在评估替代的ALL治疗策略并测试VALI介导的肺水肿形成的新疗法。 霍普金斯SCCOR申请代表了具有多学科专业知识的研究者联盟，以及将基础研究发现转化为对ALL患者的直接益处的共同目标。 在六个高度互动的核心（管理、数据管理和分析、分子病理学、犬模型核心、基因组学/基因分型和生物标志物/蛋白质组学）的支持下，六个人类和动物项目将利用最先进的分子方法进行新的表型分析 该仪器不仅可能提供迄今为止VALI关键病理生物学过程的最深入理解，而且还定义了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肺损伤的不良影响。

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.