This is a renewal of our PPG which was focused on the role of lung vascular endothelial cells (EC) as a dynamic, highly responsive, cellular barrier which is perturbed in acute lung injury. The thrust of this work has elucidated the essential role of the EC cytoskeleton, not only in barrier disruption and barrier restoration but in other lung vascular processes including EC migration, wound healing, angiogenesis, redox regulation and apoptosis. In addition to the gifted scientists who formed the critical members of our initial PPG, we have assembled an outstanding group of collaborators in this PPG renewal to focus on the EC cytoskeleton as an essential participant in lung vascular homeostasis and in the evolution of lung vascular pathobiology. This PPG renewal will utilize physiologically- and clinically-relevant stimuli (shear stress, cyclic stretch, thrombin, TNF, TGFbeta, sphingosine 1-phosplate, hyperoxia) to explore basic aspects of pulmonary vascular biology. Project 1 will extend our groups novel discovery of the multi-functiional role of EC Ser/Thr myosin light chain kinase (MLCK) in apoptosis, wound healing and barrier regulation. As multple EC functions and cytoskeletal linkages are tightly regulated by phosphorylation/dephosphorylation, Dr. Goldblums Project will provide novel information regarding the role of protein Tyr phosphatases in angiogenesis and barrier regulation. The next Project examines the unstudied area of EC barrier restoration/protection provided by the platelet-derived angiogenic factor, sphingosine 1-phosphate, via complex rearrangement of the corticl actin cytoskeleton. The last Project will provide detailed examination of the EC NADPH oxidase as a target of acute oxidant stress or agonist stimulation with regulation by the EC cytoskeleton. Finally, preliminary data from Project 5 has elucidated a highly novel role of another EC cytoskeletal component, microtubules, in EC barrier regulation which will be explored in depth and integrated into our work on the actomyosin cytoskeleton. Supported by three highly interactive Cores (Tissue/Biophysical, Molecular Resources, Imaging), we will utilize state-of-the-art molecular, biochemical, biophysical and physiological approaches that will not only likely provide the deepest understanding of the EC cytoskeleton to date, but define the role of EC cytoskeleton in critical biologic processes relevant to acute and chronic lung injury. We anticipate our work will facilitate development of new strategies and targets to limit the adverse effects of the injured pulmonary circulation.
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