Sean F. Monaghan, MD, FACS, is an Assistant Professor of Surgery at Brown University and a member of the Division of Trauma and Surgical Critical Care and the Division of Surgical Research. His research attempts to understand the biology of RNA splicing in critically ill trauma and surgical patients using Acute Respiratory Distress Syndrome (ARDS) as a model disease. He uses both human samples and animal models as well as large data sets (GTEx) with computation and molecular biology techniques in his research. Dr. Monaghan has been supported by American College of Surgeons C. James Carrico Faculty Research Fellowship and the National Institutes of Health as a Pilot Project and the Principal Investigator for Project 5 of the CardioPulmonary Vascular Biology Center of Biomedical Research Excellence.
Acute respiratory distress syndrome (ARDS) is a fatal critical illness with mortality rates remaining greater than twenty percent despite numerous clinical trials. It is therefore essential to better understand the basic mechanisms underpinning its development. 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). As such, ARDS represents an ideal model disease to understand severe critical illness and will studied in the proposed animal and human studies. ARDS is characterized by vascular permeability leading to edema and accumulation of immune cells in the lung. The increased vascular permeability is in part due to dysfunction of endothelial cells and will therefore be the focus of this project. Much work has focused on gene expression and evaluation of the protein levels with little emphasis on 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, one of interest is U1-70K. Preliminary data suggests 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 critical illness (ARDS) leads to alternative splicing of membrane bound proteins resulting in a soluble form. We hypothesize that alternative splicing seen during critical illness 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. With a better understanding of alternative RNA splicing, the long term goal is to manipulate this mechanism to improve outcomes or better predict resolution or ARDS.
Elizabeth Harrington, PhD
Associate Dean for Graduate and Postdoctoral Studies in the Division of Biology and Medicine, Professor of Medicine
Ocean State Research Institute
Providence VA Medical Center
830 Chalkstone Avenue
Providence RI 02908
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Research reported in this website was supported by the National Institute of General Medical Science of the National Institutes of Health under grant number P20GM103652.