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.
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