Genomes and Genes
Role of Sensory Neuropeptides in the Regulation of Biliary Function
Principal Investigator: GIANFRANCO D ALPINI
Affiliation: Texas A and M University
Abstract: DESCRIPTION (provided by applicant): Proliferation of cholangiocytes is critical for the maintenance of biliary mass and secretory function during the pathogenesis of chronic cholestatic liver diseases, such as primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Chronic cholestatic liver diseases (i.e., cholangiopathies) target cholangiocytes of varying size and have a heterogeneous, spotty pathology. Although sensory innervation is present in the liver as dense neural networks in the fibromuscular layer of the biliary tree, little information exists regarding its role in the regulation of biliary proliferation and function in normal and diseased states. We have obtained novel preliminary data indicating that sensory neuropeptides, released by sensory neurons innervating the biliary tree differentially, regulate the proliferation of small [via substance P (SP)] and large [via calcitonin gene related peptide (CGRP) and SP] cholangiocytes, thus suggesting that the sensory nervous system plays a potential key role in the heterogeneous proliferative responses of cholangiocytes to cholestasis and liver injury. The overall objective of this application is to determine the role that sensory innervation and sensory neuropeptides play in the maintenance of biliary mass during cholestasis and hepatoxin-induced liver damage. Based upon strong preliminary findings, we propose the novel central hypothesis that small and large cholangiocyte proliferation is regulated by sensory neuropeptides during the development of cholestasis and liver injury. Our proposed work will focus on three specific aims that have been designed to test the following working hypotheses: (i) that SP- positive sensory innervation plays a unique regulatory role in the modulation of small cholangiocyte proliferation;(ii) CGRP and SP-positive sensory innervation play a key regulatory role in large cholangiocyte proliferation;and (iii) sensory innervation and neuropeptides play a key regulatory role for controlling the differential proliferation of small and large cholangiocytes during in vivo models of liver disease. Hence, the elucidation of the intracellular mechanisms controlling the differential proliferative responses of small and large cholangiocytes to cholestasis and injury and its regulation by the sensory innervation of the liver will play a paramount role in the development of therapeutic strategies for the treatment of cholestatic liver diseases, which represent a major public health concern leading to liver transplantation or mortality. PUBLIC HEALTH RELEVANCE: The health relatedness of this application is that effective treatments are lacking for chronic cholestatic liver diseases, such as primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Chronic cholestatic liver diseases cause damage to the bile ducts of the liver. The rationale for our research is that the successful completion of the studies can ultimately be expected to provide a greater understanding of cholestatic liver disease progression and increase opportunities for the development of novel treatment paradigms for chronic liver diseases.
Funding Period: ----------------2008 - ---------------2011-
more information: NIH RePORT
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Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA
Pflugers Arch 466:1011-9. 2014..We suggest the presence of cholangiocyte-mediated intrahepatic feedback loop in addition to the enterohepatic feedback loop against bile acid biosynthesis in the liver. ..
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Department of Medicine, Scott and White Digestive Disease Research Center, Texas A and M Health Science Center College of Medicine, Temple, USA
Am J Pathol 181:804-17. 2012..These findings provide the basis for an exciting field in which the epigenomic microRNAs of hepatic cells may be manipulated with potential therapeutic benefits in human alcoholic liver diseases...
- Liver carcinogenesis: rodent models of hepatocarcinoma and cholangiocarcinomaSamuele De Minicis
Department of Gastroenterology, Universita Politecnica delle Marche, Ancona, Italy
Dig Liver Dis 45:450-9. 2013..In the second we will address models of cholangiocarcinoma developed in rats or mice by toxin administration, genetic manipulation and/or bile duct incannulation or surgery. Xenograft or syngenic models are also proposed...
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Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, University Sapienza, Rome, Italy
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Research, Central Texas Veterans Health Care System, Temple, TX 76504, USA
Am J Physiol Gastrointest Liver Physiol 305:G250-7. 2013..Therapies targeting NPY-mediated signaling may prove beneficial for the treatment of cholangiopathies...
- Recent advances in the morphological and functional heterogeneity of the biliary epitheliumYuyan Han
Department of Medicine, Division Gastroenterology, Texas A and M Health Science Center, College of Medicine, TX, USA
Exp Biol Med (Maywood) 238:549-65. 2013..After a summary section, we discuss the future perspectives that will further advance the field of the functional heterogeneity of the biliary epithelium...
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Deptartment of Internal Medicine, Texas A and M Health Science Center, College of Medicine, Temple, TX 76504, USA
Am J Physiol Gastrointest Liver Physiol 299:G1-9. 2010..This review summarizes the recent advances into our knowledge and understanding of cholangiocarcinoma and highlights potential novel therapeutic strategies that may prove useful to treat this deadly disease...
- Regulation of placenta growth factor by microRNA-125b in hepatocellular cancerGianfranco Alpini
Department of Medicine and Scott and White Digestive Disease Research Center, Texas A and M HSC COM and Scott and White Hospital, Temple, TX 76504, USA
J Hepatol 55:1339-45. 2011..microRNAs (miRNAs) are a class of small noncoding RNAs that can regulate gene expression by translation repression or mRNA degradation. Our aim was to evaluate the role of aberrantly expressed miRNAs in hepatocellular cancer (HCC)...
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Temple, TX 76504, USA
Am J Physiol Gastrointest Liver Physiol 301:G634-43. 2011..In vitro, melatonin decreased the proliferation, cAMP levels, and PKA phosphorylation, decreases that were blocked by luzindole. Melatonin may be important in the management of biliary hyperplasia in human cholangiopathies...
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Division Research, Central Texas Veterans Health Care System, Tempe, USA
Am J Physiol Gastrointest Liver Physiol 301:G623-33. 2011..There is dysregulation of the AANAT/ASMT/melatonin → melatonin receptor axis in CCA, which inhibited melatonin secretion and subsequently enhanced CCA growth...
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Division of Research, Central Texas Veterans Health Care System, Scott and White and Texas A and M Health Science Center, College of Medicine, Temple, Texas 76504, USA
Gut 61:753-64. 2012..Cholangiocarcinoma is a biliary cancer with limited treatment options. Histamine interacts with four G-protein coupled receptors, H1-H4 histamine receptors (HRs)...
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Department of Medicine and Scott and White Digestive Disease Research Center, Texas A and M Health Science Center, College of Medicine, and Scott and White Hospital, Temple, TX 76504, USA
Hepatology 55:209-21. 2012..Levels of MMP-2, MMP-9, and miR-181b were also up-regulated in rat liver and isolated cholangiocytes after PH...
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Department of Internal Medicine, Scott and White Digestive Disease Research Center, Scott and White Hospital and Texas A and M Health Science Center, College of Medicine, Temple, TX, USA
Lab Invest 92:282-94. 2012..The activation of differential signaling mechanisms targeting small and large cholangiocytes is important for repopulation of the biliary epithelium during pathologies affecting different-sized bile ducts...
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Scott and White Digestive Disease Research Center, TX, USA
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Department of Cell and Molecular Physiology, University of North Carolina School of Medicine, Chapel Hill, NC, USA
Hepatology 53:1035-45. 2011..Recognition of maturational lineage biology and its regulation by these multiple mechanisms offers new understandings of liver biology, pathologies, and strategies for regenerative medicine and treatment of liver cancers...
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Department of Medicine, College of Medicine, Temple, Texas, USA
Am J Pathol 178:472-84. 2011..We also review what is currently known about the neuroendocrine phenotypes of cholangiocytes in human cholestatic liver diseases (ie, cholangiopathies) that are characterized by ductular reaction...
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Department of Medicine, Scott and White and Texas A and M Health Science Center, Temple, TX 76504, USA
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Department of Gastroenterology, Universita Politecnica delle Marche, Ancona, Italy
Liver Int 29:1031-42. 2009..ET-1 inhibits secretin-stimulated ductal secretion (hallmark of cholangiocyte growth) of cholestatic rats by interaction with ET receptors...
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Department of Experimental Medicine, University of L Aquila, L Aquila, Italy
Int J Cancer 125:565-76. 2009..CAPE both in vivo and in vitro decreases the growth of CCH cells by increasing apoptosis. These results demonstrate that CAPE might be an important therapeutic tool in the treatment of CCH...
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School of Biological Sciences, The Univerity of Hong Kong, Pokfulam Rd, Hong Kong
Am J Physiol Gastrointest Liver Physiol 297:G90-7. 2009..Because secretin is a key hormone that stimulates bile flow in cholangiocytes, this pathway thus provides a novel means to modulate secretin-stimulated choleresis in response to intraduodenal bile acids...
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Department of Medicine, Division Gastroenterology, Texas A and M Health Science Center, College of Medicine, Texas, USA
Am J Physiol Gastrointest Liver Physiol 297:G11-26. 2009..Silencing of FSH gene decreases cholangiocyte proliferation and ERK1/2 and Elk-1 phosphorylation. Modulation of cholangiocyte FSH expression may be important for the management of cholangiopathies...
- Differentially expressed adenylyl cyclase isoforms mediate secretory functions in cholangiocyte subpopulationMario Strazzabosco
Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine and Liver Center, New Haven, CT 06520, USA
Hepatology 50:244-52. 2009..Treatment with lipopolysaccharide or alpha-naphthylisothiocyanate increased expression of AC7 and sAC but decreased expression of the other ACs...
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Scott and White Digestive Disease Research Center, Texas A and M Health Science Center College of Medicine, Temple, TX 76504, USA
Mol Cancer Res 7:1704-13. 2009..RAMH inhibits cholangiocarcinoma growth by PKCalpha-dependent ERK1/2 dephosphorylation. Modulation of PKCalpha by histamine receptors may be important in regulating cholangiocarcinoma growth...
- Vascular factors, angiogenesis and biliary tract diseaseShannon S Glaser
Scott and White Digestive Disease Research Center, Department of Medicine, Division Gastroenterology, Texas A and M Health Science Center, Temple, Texas, USA
Curr Opin Gastroenterol 26:246-50. 2010....
- Recent advances in the regulation of cholangiocyte proliferation and function during extrahepatic cholestasisShannon S Glaser
Digestive Disease Research Center, Scott and White, Texas A and M Health Science Center, 702 SW H K Dodgen Loop, Temple, TX 76504, USA
Dig Liver Dis 42:245-52. 2010....
- After damage of large bile ducts by gamma-aminobutyric acid, small ducts replenish the biliary tree by amplification of calcium-dependent signaling and de novo acquisition of large cholangiocyte phenotypesRomina Mancinelli
Texas A and M Health Science Center, Medical Research Building, Temple, TX 76504, USA
Am J Pathol 176:1790-800. 2010..Therefore, in pathologies of large ducts, small ducts replenish the biliary epithelium by amplification of Ca(2+)-dependent signaling and acquisition of large cholangiocyte phenotypes...
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Scott and White Digestive Disease Research Center, Scott and White, Temple, TX 76504, United States
Dig Liver Dis 42:709-17. 2010..The potential regulation of VEGF and VEGF receptor expression and secretion by bile acids in BDL with HAL is unknown...
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Scott and White Digestive Disease Research Center, Temple, Texas, USA
Am J Physiol Gastrointest Liver Physiol 299:G769-77. 2010....
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Texas A and M Health Science Center College of Medicine, 702 SW H K Dodgen Loop, Temple, TX, 76504 or
Am J Physiol Cell Physiol 300:C1078-89. 2011..We demonstrated that NPY expression is upregulated in cholangiocarcinoma, which exerts local control on tumor cell proliferation and invasion. Modulation of NPY secretion may be important for the management of cholangiocarcinoma...
- Activation of alpha(1) -adrenergic receptors stimulate the growth of small mouse cholangiocytes via calcium-dependent activation of nuclear factor of activated T cells 2 and specificity protein 1Gianfranco Alpini
Central Texas Veterans Health Care System, TX, USA
Hepatology 53:628-39. 2011..Phenylephrine stimulated small cholangiocyte proliferation is regulated by Ca(2+) -dependent activation of NFAT2 and Sp1...
- Exendin-4, a glucagon-like peptide 1 receptor agonist, protects cholangiocytes from apoptosisM Marzioni
Department of Gastroenterology, Universita Politecnica delle Marche, Nuovo Polo Didattico, Via Tronto 10, 60020 Ancona, Italy
Gut 58:990-7. 2009..Exendin-4 is now employed in humans as a novel therapy for diabetes. The aim of the present study was to verify whether exendin-4 is effective in preventing cholangiocyte apoptosis...