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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-PPG-N (O1))
Program Officer
Denholm, Elizabeth M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Wang, Ting; Brown, Mary E; Kelly, Gabriel T et al. (2018) Myosin light chain kinase ( MYLK) coding polymorphisms modulate human lung endothelial cell barrier responses via altered tyrosine phosphorylation, spatial localization, and lamellipodial protrusions. Pulm Circ 8:2045894018764171
Wang, X; Wang, L; Garcia, J G N et al. (2018) The Significant Role of c-Abl Kinase in Barrier Altering Agonists-mediated Cytoskeletal Biomechanics. Sci Rep 8:1002
Oita, Radu C; Camp, Sara M; Ma, Wenli et al. (2018) Novel Mechanism for Nicotinamide Phosphoribosyltransferase Inhibition of TNF-?-mediated Apoptosis in Human Lung Endothelial Cells. Am J Respir Cell Mol Biol 59:36-44
Szilágyi, Keely L; Liu, Cong; Zhang, Xu et al. (2017) Epigenetic contribution of the myosin light chain kinase gene to the risk for acute respiratory distress syndrome. Transl Res 180:12-21
Wang, X; Bleher, R; Wang, L et al. (2017) Imatinib Alters Agonists-mediated Cytoskeletal Biomechanics in Lung Endothelium. Sci Rep 7:14152
Shekhawat, Gajendra S; Dudek, Steven M; Dravid, Vinayak P (2017) Development of ultrasound bioprobe for biological imaging. Sci Adv 3:e1701176
Mascarenhas, Joseph B; Tchourbanov, Alex Y; Fan, Hanli et al. (2017) Mechanical Stress and Single Nucleotide Variants Regulate Alternative Splicing of the MYLK Gene. Am J Respir Cell Mol Biol 56:29-37
Belvitch, Patrick; Brown, Mary E; Brinley, Brittany N et al. (2017) The ARP 2/3 complex mediates endothelial barrier function and recovery. Pulm Circ 7:200-210
Camp, Sara M; Chiang, Eddie T; Sun, Chaode et al. (2016) ""Pulmonary Endothelial Cell Barrier Enhancement by Novel FTY720 Analogs: Methoxy-FTY720, Fluoro-FTY720, and ?-Glucuronide-FTY720"". Chem Phys Lipids 194:85-93
Rojo de la Vega, Montserrat; Dodson, Matthew; Gross, Christine et al. (2016) Role of Nrf2 and Autophagy in Acute Lung Injury. Curr Pharmacol Rep 2:91-101

Showing the most recent 10 out of 270 publications