Professor
Internal Medicine
Systems Biology and Translational Medicine

Phone: 254-742-7044
Fax: 254-771-5725
Email: GAlpini@medicine.tamhsc.edu

Education

B.S., Classical Studies, 1976, Terenzio Mamiani, Rome, Italy

Ph.D., Chemistry and Pharmaceutical Technologies, 1984, University of Studies of Rome "La Sapienza," Rome, Italy

Research Interests

My research focuses on the pathophysiology of intrahepatic bile duct epithelial cells or cholangiocytes, which line the intrahepatic biliary tree inside the liver. Cholangiocytes play a key role in the modification of the bile (secreted by hepatocytes) by a series of reabsorptive and secretory processes under both spontaneous and hormone-regulated conditions. Cholangiocytes have also the capacity to selectively proliferate following the application of pathological perturbations, such as bile duct ligation. Cholangiocyte proliferation is observed in virtually all human cholestatic liver diseases. The Two Major Objectives of my research program are: (i) to identify and functionally characterize the different sized segments of the intrahepatic biliary tree which are differentially involved in secretory and proliferative processes under normal and pathophysiological states which is of particular importance since cholangiocyte proliferation in human cholestatic liver disease is restricted to specific-sized ducts; and (ii) to define the coordinated and complex series of factors which regulate cholangiocyte proliferation in liver disease.

My laboratory uses several experimental approaches to investigate cholangiocyte proliferative and secretory processes. We have developed novel techniques for isolating distinct subpopulations of cholangiocytes and intrahepatic bile duct fragments and have begun to study secretory and proliferative processes of cholangiocytes and bile duct fragments. In these studies, we use a number of state of the art cellular, molecular (e.g., quantitative gene expression by RNase protection assay), biochemical (e.g., measurement of second messenger systems), immunological and physiological techniques (e.g., studies of biliary physiology, measurement of Cl- efflux and Cl-/HCO3- exchanger activity) to assess cholangiocyte proliferation and secretion. The factors/mechanisms regulating cholangiocyte proliferation in liver diseases is unknown. To elucidate this important issue, we are currently examining the in vivo and in vitro effects of a number of possible factors gastrointestinal hormones (e.g., secretin, gastrin and somatostatin), bile acids (e.g., taurocholate and taurolithocholate), growth factors (e.g., epidermal growth factors and hepatocyte growth factor), cAMP agonist and antagonists, cholinergic and adrenergic innervation in the modulation of cholangiocyte proliferation in liver disease.

My research focuses on the pathophysiology of intrahepatic bile duct epithelial cells or cholangiocytes, which line the intrahepatic biliary tree inside the liver. Cholangiocytes play a key role in the modification of the bile (secreted by hepatocytes) by a series of reabsorptive and secretory processes under both spontaneous and hormone-regulated conditions. Cholangiocytes have also the capacity to selectively proliferate following the application of pathological perturbations, such as bile duct ligation. Cholangiocyte proliferation is observed in virtually all human cholestatic liver diseases. The Two Major Objectives of my research program are: (i) to identify and functionally characterize the different sized segments of the intrahepatic biliary tree which are differentially involved in secretory and proliferative processes under normal and pathophysiological states which is of particular importance since cholangiocyte proliferation in human cholestatic liver disease is restricted to specific-sized ducts; and (ii) to define the coordinated and complex series of factors which regulate cholangiocyte proliferation in liver disease.

My laboratory uses several experimental approaches to investigate cholangiocyte proliferative and secretory processes. We have developed novel techniques for isolating distinct subpopulations of cholangiocytes and intrahepatic bile duct fragments and have begun to study secretory and proliferative processes of cholangiocytes and bile duct fragments. In these studies, we use a number of state of the art cellular, molecular (e.g., quantitative gene expression by RNase protection assay), biochemical (e.g., measurement of second messenger systems), immunological and physiological techniques (e.g., studies of biliary physiology, measurement of Cl- efflux and Cl-/HCO3- exchanger activity) to assess cholangiocyte proliferation and secretion. The factors/mechanisms regulating cholangiocyte proliferation in liver diseases is unknown. To elucidate this important issue, we are currently examining the in vivo and in vitro effects of a number of possible factors gastrointestinal hormones (e.g., secretin, gastrin and somatostatin), bile acids (e.g., taurocholate and taurolithocholate), growth factors (e.g., epidermal growth factors and hepatocyte growth factor), cAMP agonist and antagonists, cholinergic and adrenergic innervation in the modulation of cholangiocyte proliferation in liver disease.

The long-term goals of the laboratory are to develop new therapeutic strategies based upon increasing our knowledge of mechanisms of cholangiocyte transport and proliferation. The high prevalence of liver disease and the almost universal presence of proliferation and/or destruction of intrahepatic bile ducts underscore the significance of the studies in human liver disease.

Selected Publications

H Francis, G LeSage, S DeMorrow, D Alvaro, Y Ueno, J Venter, S Glaser, MG Mancino, L Marucci, A Benedetti, and G Alpini.  The a-2 adrenergic receptor agonist, UK 14,304, inhibits secretin-stimulated ductal secretion by impairing activation of the cAMP system.  Am J Physiol Cell Physiol 293:C1252-62, 2007.

S DeMorrow, H Francis, E Gaudio, Y Ueno, J Venter, P Onori, A Franchitto, B Vaculin, S Vaculin, and G Alpini. Anandamide inhibits cholangiocyte hyperplastic proliferation via activation of thioredoxin 1/redox factor 1 and AP-1 activation.  Am J Physiol, 294:G506-519, 2008.

S DeMorrow, S Glaser,  Francis, J Venter, B Vaculin, S Vaculin, and G Alpini. Opposing actions of endocannabinoids on cholangiocarcinoma growth: recruitment of death receptor into lipid rafts.  J Biol Chem 282: 13098-13113, 2007.

H Francis, A Franchitto, Y Ueno, S Glaser, S DeMorrow, E Gaudio, D Alvaro, G Fava, M Marzioni, J Venter, BT Vaculin, and G Alpini.  H3 histamine receptor agonist inhibits cholangiocyte growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2 /ELK-1 pathway.  Lab Invest 87: 473-87, 2007.

E Gaudio, B Barbaro, D Alvaro, S Glaser, H Francis, Y Ueno, C J Meininger, A Franchitto, P Onori, M Marzioni, S Taffetani, G Fava, G Stoica, J Venter, R Reichenbach, S DeMorrow, R Summers, and G Alpini.  Vascular endothelial growth factor stimulates rat cholangiocyte proliferation via an autocrine mechanism.  Gastroenterology 130:1270-182, 2006.

G Fava, L Marucci, S Glaser, H Francis, S DeMorrow, R Reichenbach, A Benedetti, D Alvaro, J Venter, C Meininger, T Patel, S Taffetani, M Marzioni, R Summers, and G Alpini.  Gamma-aminobutyric acid inhibits cholangiocarcinoma growth by cAMP-dependent regulation of the PKA/ERK1/2 pathway.  Cancer Research 65:11437-1146, 2005.