Acute respiratory distress syndrome (ARDS) is a fatal critical illness with mortality rates greater than twenty percent despite numerous clinical trials. It is therefore essential to develop better understanding of the basic mechanisms of development of ARDS. ARDS is also unique in that it is a common pathway that occurs after many disease processes that result in critical illness (shock from trauma or sepsis, burns, pancreatitis). ARDS is characterized by vascular permeability leading to edema and accumulation of immune cells in the lung. The increased vascular permeability is due to endothelial cell dysfunction and is the focus of this project. Much work has focused on gene and protein expression with little known about changes in RNA splicing. RNA splicing is a basic molecular function that occurs in all cells directly after RNA transcription, but before protein translation in which introns are removed and exons are joined together. Over 90% of human genes with multiple exons have alternative splicing events. With such a high rate of variation from the transcribed gene to the produced protein, splicing must be under exquisite control, particularly in times of critical illness. Numerous proteins are involved in the control of RNA splicing, including U1-70K. Preliminary data suggest that in the lung there is no difference in gene expression, but rather multiple sites of alternative splicing of U1-70K. This is similar to previous work showing that ARDS leads to alternative splicing of membrane bound proteins resulting in a soluble form. We hypothesize that in ARDS alternative splicing alters the protein isoforms of U1-70K in endothelial cells. This change in the isoforms, in turn, results in the microvascular permeability and sequestration of edema and immune cells in the lungs during ARDS.
Aim 1 will determine the isoforms of U1- 70K in endothelial cells and whether these isoforms are correlated with lung vascular permeability using a mouse model of ARDS caused by cecal ligation and puncture.
Aim 2 will determine the effects of the physiological conditions (high acid, low oxygen) seen in ARDS on the U1-70K isoforms and endothelial cell barrier dysfunction.
Aim 3 will assess if U1-70K alternative splicing events present in the pre-clinical model are present in samples from humans with critical illness. Better understanding of alternative RNA splicing in ARDS will allow manipulation of this mechanism to improve outcomes and improve prediction of resolution of this devastating syndrome.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Ocean State Research Institute, Inc.
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Baird, Grayson L; Archer-Chicko, Christine; Barr, R Graham et al. (2018) Lower DHEA-S levels predict disease and worse outcomes in post-menopausal women with idiopathic, connective tissue disease- and congenital heart disease-associated pulmonary arterial hypertension. Eur Respir J 51:
Shah, Nishant R; Blankstein, Ron; Villines, Todd et al. (2018) Coronary CTA for Surveillance of Cardiac Allograft Vasculopathy. Curr Cardiovasc Imaging Rep 11:26
Monaghan, Sean F; Banerjee, Debasree; Chung, Chun-Shiang et al. (2018) Changes in the process of alternative RNA splicing results in soluble B and T lymphocyte attenuator with biological and clinical implications in critical illness. Mol Med 24:32
Potz, Brittany A; Scrimgeour, Laura A; Pavlov, Vasile I et al. (2018) Extracellular Vesicle Injection Improves Myocardial Function and Increases Angiogenesis in a Swine Model of Chronic Ischemia. J Am Heart Assoc 7:
Zhou, Yang; He, Chuan Hua; Yang, Daniel S et al. (2018) Galectin-3 Interacts with the CHI3L1 Axis and Contributes to Hermansky-Pudlak Syndrome Lung Disease. J Immunol 200:2140-2153
Zhao, Haifeng; Dennery, Phyllis A; Yao, Hongwei (2018) Metabolic reprogramming in the pathogenesis of chronic lung diseases, including BPD, COPD, and pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 314:L544-L554
Chambers, Eboni; Rounds, Sharon; Lu, Qing (2018) Pulmonary Endothelial Cell Apoptosis in Emphysema and Acute Lung Injury. Adv Anat Embryol Cell Biol 228:63-86
Sellke, Nicholas; Kuczmarski, Alex; Lawandy, Isabella et al. (2018) Enhanced coronary arteriolar contraction to vasopressin in patients with diabetes after cardiac surgery. J Thorac Cardiovasc Surg 156:2098-2107
Fallon, Eleanor A; Biron-Girard, Bethany M; Chung, Chun-Shiang et al. (2018) A novel role for coinhibitory receptors/checkpoint proteins in the immunopathology of sepsis. J Leukoc Biol :
Aldosari, Sarah; Awad, Maan; Harrington, Elizabeth O et al. (2018) Subcellular Reactive Oxygen Species (ROS) in Cardiovascular Pathophysiology. Antioxidants (Basel) 7:

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