The goal of this project is to determine the role of transforming growth factor-beta (TGF-beta) in the pathogenesis of biliary atresia. Our initial experiments are designed to establish a durable and reproducible animal model of biliary atresia. We will use these preliminary experiments to determine the time course of TGF-beta activation as well as expression of one of the most important mediators of TGF-beta function, the integrin alpha-v beta-6. This integrin has been shown to mediate TGF-beta function and hepatic fibrosis in an adult mouse bile duct ligation model, and we postulate that it will play a similar role in the fibrosis associated with biliary atresia. Downstream mediators of TGF-beta function will also be evaluated, including the SMAD family of proteins, plasminogen activator inhibitors, and the tissue inhibitors of the metalloproteinases. Subsequent studies will address the role of these mediators. The approach will be to employ different strategies designed to inhibit function of each mediator, and then determine what impact blockade has on the development of the fibrosis associated with biliary atresia. The final set of experiments will investigate whether TGF-beta blockade or blockade of its mediators administered after the onset of biliary atresia has any role in preventing the hepatic cirrhosis associated with the disease.
The specific aims are: 1. To determine the extent and time course for expression of activated TGF-beta, integrin alpha-v beta- 6, and other important mediators of TGF-beta function in an animal model of biliary atresia;2. To determine the role of TGF-beta and its mediators in the pathogenesis of experimental biliary atresia by employing different strategies for inhibiting function;and 3. To determine whether TGF-beta blockade or blockade of its mediators after development of biliary atresia can arrest the progression of the disease. Biliary atresia is a progressive obliteration of the bile ducts and is the most common indication for liver transplantation in children. Current therapy fails to prevent liver failure, and thus fails to prevent the need for liver transplantation, in approximately two-thirds of all children stricken with the disease. This proposal is designed to help determine which mediators are important in the development of the liver failure associated with biliary atresia, and whether blocking these mediators may be useful in preventing liver failure.
|Iordanskaia, Tatiana; Malesevic, Miroslav; Fischer, Gunter et al. (2015) Targeting extracellular cyclophilins ameliorates disease progression in experimental biliary atresia. Mol Med :|
|Iordanskaia, Tatiana; Koeck, Emily; Rossi, Christopher et al. (2014) Integrin Î²-8, but not Î²-5 or -6, protein expression is increased in livers of children with biliary atresia. J Pediatr Gastroenterol Nutr 59:679-83|
|Iordanskaia, Tatiana; Hubal, Monica J; Koeck, Emily et al. (2013) Dysregulation of upstream and downstream transforming growth factor-* transcripts in livers of children with biliary atresia and fibrogenic gene signatures. J Pediatr Surg 48:2047-53|
|Nadler, Evan P; Li, Xiaolu; Onyedika, Emeka et al. (2010) Differential expression of hepatic fibrosis mediators in sick and spontaneously recovered mice with experimental biliary atresia. J Surg Res 159:611-7|