The long-term goal of our studies is to understand the role of biliary epithelium in the repair and regeneration of the liver after damage. Inherited cholangiopathies with identified genetic defects serve as model diseases to elucidate the fundamental pathophysiological mechanisms. The previously funded proposal focused on polycystic liver disease associated to Adult Dominant Polycystic Kidney Disease (PLD-ADPKD) as a paradigm for the role of angiogenic signaling in biliary diseases. We uncovered mechanisms that may be relevant for the pathogenesis of other congenital and acquired liver diseases. In fact, using mice models with inducible defects of polycystins, we found that: 1) the cystic epithelium produces VEGF and expresses its cognate receptor VEGFR2;2) VEGF-mediated stimulation of VEGFR2 results in increased ERK1/2-dependent proliferation of the cystic epithelium, 3) PC2-defective cystic cholangiocytes, altered cellular Ca2+ homeostasis and a cAMP- dependent increase in PKA/Ras/Raf/ERK signaling results in mTOR/HIF-1?-mediated stimulation of VEGF production, 4) in response to stimuli able to deplete ER Ca2+ stores, PC2 participates in store-operated Ca2+ entry (SOCE);5) if PC2 is defective, an alternative pathway is activated (store-operated cAMP production - SOcAMP), leading to an inappropriate overproduction of cAMP;6) VEGF/VEGFR2 play a key role on cyst growth and expansion through paracrine effects on pericystic vascular cells, and autocrine stimulation of the cystic epithelium proliferation. These findings are the basis of this new proposal which main hypothesis is that the mechanism linking PC2 to VEGF secretion and VEGFR2 expression identified in PLD-ADPKD is of general relevance in biliary pathophysiology. We will address this hypothesis through three specific aims: 1) to better understand the interactions between PC2 function store-operated Ca2+ entry and inappropriate production of cAMP, 2) to study if PC2 expression in WT cholangiocytes can be modulated by cell stressors, thereby reproducing the changes seen in PC2-defective cells;3) to study the mechanisms leading to VEGFR2 expression in cystic and reactive cholangiocytes, and to elucidate the role of VEGF in the branching morphogenesis of the biliary epithelium during liver repair. These studies will address the novel idea that PC2 play a pivotal role in the regulation of cholangiocyte response to biliary damage acquired cholangiopathies, and that VEGF secreted by reactive cholangiocytes is a major factor in liver repair. Furthermore, our studies will increase understanding of VEGF/VEGFR2 signaling in epithelia and will address a fundamental mechanism in congenital and acquired cholangiopathies. Understanding the pathophysiology of cholangiopathies is a fundamental step for preserving liver function and prolonging the survival of patients

Public Health Relevance

Cholangiopathies are a group of genetic and acquired liver diseases responsible for significant morbidity and mortality among liver patients. In this proposal we will test the novel idea that Polycystin-2 (PC2), the protein mutated in ADPKD, can be modulated in response to biliary damage/repair and stimulate reparative VEGF secretion and VEGFR2 expression. Understanding of VEGF/VEGFR2 signaling in epithelia addresses a fundamental mechanism in congenital and acquired cholangiopathies.

National Institute of Health (NIH)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Doo, Edward
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Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
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Geisler, Fabian; Strazzabosco, Mario (2015) Emerging roles of Notch signaling in liver disease. Hepatology 61:382-92
Strazzabosco, Mario; Fabris, Luca; Albano, Emanuele (2014) Osteopontin: a new player in regulating hepatic ductular reaction and hepatic progenitor cell responses during chronic liver injury. Gut 63:1693-4
Morell, Carola Maria; Strazzabosco, Mario (2014) Notch signaling and new therapeutic options in liver disease. J Hepatol 60:885-90
Strazzabosco, Mario; Fabris, Luca (2014) Neural cell adhesion molecule and polysialic acid in ductular reaction: the puzzle is far from completed, but the picture is becoming more clear. Hepatology 60:1469-72
Cadamuro, Massimiliano; Nardo, Giorgia; Indraccolo, Stefano et al. (2013) Platelet-derived growth factor-D and Rho GTPases regulate recruitment of cancer-associated fibroblasts in cholangiocarcinoma. Hepatology 58:1042-53
Morell, Carola Maria; Fiorotto, Romina; Fabris, Luca et al. (2013) Notch signalling beyond liver development: emerging concepts in liver repair and oncogenesis. Clin Res Hepatol Gastroenterol 37:447-54
Spirli, Carlo; Locatelli, Luigi; Morell, Carola M et al. (2013) Protein kinase A-dependent pSer(675) -*-catenin, a novel signaling defect in a mouse model of congenital hepatic fibrosis. Hepatology 58:1713-23
Morell, Carola M; Fabris, Luca; Strazzabosco, Mario (2013) Vascular biology of the biliary epithelium. J Gastroenterol Hepatol 28 Suppl 1:26-32
Spirli, Carlo; Locatelli, Luigi; Fiorotto, Romina et al. (2012) Altered store operated calcium entry increases cyclic 3',5'-adenosine monophosphate production and extracellular signal-regulated kinases 1 and 2 phosphorylation in polycystin-2-defective cholangiocytes. Hepatology 55:856-68
Strazzabosco, Mario; Fabris, Luca (2012) Development of the bile ducts: essentials for the clinical hepatologist. J Hepatol 56:1159-70

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