The long-term goal of this study is to identify a potential innovative therapeutic target to prevent or treat Acute Respiratory Distress Syndrome (ARDS), a condition associated with systemic inflammation and characterized by extensive lung epithelial damage leading to protein enriched fluid influx into the lung alveolar space and compromised ventilation [1, 2]. The rapid progression of acute lung injury at the onset of ARDS is one of the reasons responsible for the high mortality of ARDS . A variety of strategies to treat and manage ARDS has been extensively investigated. However, patient survival has not been improved. Based on the previous work of our laboratory and numerous studies that identify the cell survival phosphatidylinositol 3'-kinase (PI3K)/Akt pathway as a vital survival axis in the lung epithelium, we focused on this pathway as a molecular target to prevent lung epithelium dysfunction [4-6]. Phosphatase and Tensin homolog deleted on chromosome Ten (PTEN) is a phosphase that is known to be a negative regulator of the PI3K/Akt survival pathway by dephosphorylation of PI(3,4,5)P3 at the 3 position in the inositol ring thereby inactivating this second messenger [7, 8]. PTEN is enriched in the lung epithelium as observed in our preliminary data. The Knoell laboratory previously reported that activation of the PI3K/Akt pathway promotes lung epithelial cell survival during inflammatory stress . Based on this, we hypothesized that inhibition of PTEN by specific PTEN inhibitors would be a rational therapeutic strategy to facilitate normal lung epithelium cell function under stress conditions. The PTEN inhibitor, bisperoxovanadium, was first reported in 2004 documenting PTEN target specificity in cell culture models . In our study, the same PTEN inhibitor and a related analogue were utilized and studied for their in vitro and in vivo potential to inhibit PTEN, activate the PI3K/Akt signaling axis and/or other downstream signaling pathways of PTEN, and restore lung epithelial function either before or after insult.
|Advisor:||Knoell, Daren, Dalton, James|
|Commitee:||Schmittgen, Thomas, St-Pierre, Normand, Sun, Duxin, Tridandapani, Susheella|
|School:||The Ohio State University|
|School Location:||United States -- Ohio|
|Source:||DAI-B 78/11(E), Dissertation Abstracts International|
|Subjects:||Pharmacology, Pharmacy sciences|
|Keywords:||Acute lung injury, Lung epithelium, PTEN inhibition, Protection, Wound repair|
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