Agnieszka Swiatecka-Urban, M.D.
Research Interest: The role of endocytic trafficking in regulation of transmembrane protein function in human epithelial cells


One of the two main research interests in our laboratory is to elucidate the spacial and temporal regulation of the endocytic trafficking of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in order to identify a therapeutic target for the most common, fatal genetic disease, cystic fibrosis (CF). CFTR is expressed in the apical plasma membrane in epithelial cells where it functions as a cAMP-activated Cl- channel. Absence of the CFTR function in the airway impairs the mucociliary clearance and leads to chronic infection with Pseudomonas aeruginosa, inflammation, tissue damage, impaired lung function, and eventually death. Consequently, lung disease is the major cause of morbidity, and mortality in CF patients. The most common mutation in CFTR is ΔF508.ΔF508-CFTR does not fold properly and most is retained within the endoplasmic reticulum (ER) and is subsequently degraded. Because the small amount of ΔF508-CFTR that traffics to the plasma membrane is partially functional as a Cl- channel, increasing the expression of ΔF508-CFTR in the apical membrane may serve as a future therapeutic option for the CF patients. The mechanism of reduced plasma membrane expression of ΔF508-CFTR is not completely understood, in part, because the protein-protein interactions that facilitate the endocytic trafficking of the apical membrane CFTR have not been completely elucidated. Our research focuses on elucidating novel endocytic adaptors that regulate trafficking of CFTR at the apical membrane in human airway epithelial cells. Furthermore, we study the effects of the ΔF508 mutation on these adaptor proteins.

Our second main research interest is to elucidate the mechanisms that regulate the slit diaphragm integrity in order to identify useful therapeutic targets for proteinuria and nephrotic syndrome (NS). Nephrin is a transmembrane protein and cell adhesion molecule expressed at the modified tight junction, called the slit diaphragm, which is localized between the interdigitating foot processes of the glomerular epithelium (podocytes) in the kidney. The extracellular domain of nephrin facilitates formation of homophilic nephrin interactions between the adjacent foot processes that are essential for the integrity of the slit diaphragm. Reduced expression and altered intracellular localization of nephrin lead to retraction and effacement of the foot processes, proteinuria, and NS. Mutations in the nephrin gene are responsible for congenital NS while downregulation of nephrin expression correlates with the degree of proteinuria in diabetic nephropathy, the leading cause of chronic renal failure in the US. Our laboratory studies the role of nephrin endocytic trafficking in the dynamic regulation of the slit diaphragm integrity. Furthermore, we study the protein-protein interactions that facilitate the endocytic trafficking of nephrin.



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