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SEC10 INACTIVATION RESULTS IN CELL DEATH AND UPREGULATION OF FN14 DURING URETER DEVELOPMENT
|Title:||SEC10 INACTIVATION RESULTS IN CELL DEATH AND UPREGULATION OF FN14 DURING URETER DEVELOPMENT|
|Contributors:||Fogelgren, Benjamin (advisor)|
Cell and Molecular Biology (department)
|Publisher:||University of Hawai'i at Manoa|
|Abstract:||Congenital malformations that obstruct the urinary tract are the leading cause of kidney disease in children, and these obstructions most commonly occur in the upper ureter. We have recently characterized a novel Sec10 conditional knockout mouse (Sec10-CKO) that is the first animal model of prenatal ureter obstructions that are commonly seen in humans. Sec10 CKO mice presented with a monolayered epithelium, lacked uroplakin expression, and cell death which ultimately led to the formation of an obstruction. The Sec10 gene is one of the central subunits of the exocyst, a highly conserved protein complex that mediates the trafficking and docking of certain intracellular vesicles. The ureter obstruction in these mice is caused by the failure of differentiation of the epithelial cells that line the ureter, called urothelial cells. |
This suggest that Sec10 and the exocyst complex may regulate key developmental pathways that are involved in urothelial differentiation.
To better investigate the role of Sec10 in ureter development, we have established an ex vivo ureter explant organ culture model where we can follow differentiation of the mono-layered urothelial progenitors until maturity. This ex vivo model also allows us to target various signaling pathways using small molecule inhibitors and then measure for potential effects it has on urothelial differentiation. Results confirmed that Sec10 knockout in urothelial cells prevented differentiation, stratification and led to cell detachment and death. Treatment with a retinoic acid inhibitor also led to a similar phenotype with an absence of uroplakin gene expression in explanted ureters and the sloughing of cells into the luminal space but no cell death. This suggests that the urothelial cells may be undergoing some other form of mechanical stress that results in the death of these cells.
To investigate molecular changes that are occurring during urothelial cell death, microarray analysis was performed to determine differential gene expression. The results of the microarray analysis showed a significant upregulation of Fn14; a receptor that is upregulated in response to stress.
|Description:||M.S. Thesis. Ph.D. Thesis. University of Hawaiʻi at Mānoa 2019|
|Rights:||All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.|
|Appears in Collections:||
M.S. - Cell and Molecular Biology|
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