VENTILATOR ASSOCIATED LUNG INJURY: MOLECULAR APPROACHES

呼吸机相关肺损伤：分子方法

• 批准号: 7116399
• 负责人: Roy G. Brower
• 金额: $ 437.44万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7116399
• 关键词: adult respiratory distress syndrome; clinical research; molecular pathology; respirators

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.

描述（由申请人提供）：急性肺损伤（全）是在败血症和其他全身性炎症性疾病的背景下发生的毁灭性疾病，机械通气介导的压力明确贡献了对不良患者结果的压力。 这种SCCOR的应用集中在理解机械通气和所有患者中提高的发病率和死亡率之间的复杂相互作用。 与人类基因组的映射一致，高吞吐量技术现在为有意义的翻译研究提供了潜力，以解决（i）（i）理性机械通气策略的分子基础，以及（ii）机械压力与遗传感染患者中病理基因表达的激活的关系。 由于所有和与呼吸机相关的所有（VALI）可能是异质分子过程的表现，因此它是这种SCCOR应用的主题基础，基因组技术的进步为不仅表征对Vali的肺反应不仅具有增加的敏感性和清晰度的表征，而且还可以识别出新的分子靶标的肺反应。 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学研究（具有严格的表型表征），并在大量具有全部良好型的患者中表征了潜在的重要多态性。 重要的是，这些研究将由旨在评估所有通气策略的创新研究补充，并测试Vali介导的肺水肿形成的新疗法。 霍普金斯SCCOR的应用代表了具有多学科专业知识的研究人员的联盟，也是将基础研究发现转化为所有人的直接利益的共同目标。 在六个高度互动核心（给药，数据管理和分析，分子病理学，犬类模型核心，基因组/基因分型以及生物标志物/蛋白质组学）的支持下，六个人类和动物项目将利用新型的分子方法和新的分子方法 仪器不仅可能会对迄今为止瓦利的关键病理生物学过程提供最深刻的理解，还可以定义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有助于制定新的策略，发现新的治疗靶标，并定义新的预后指标，这将限制机械通气对急性损伤肺的不利影响。