Role of Sensory Neuropeptides in the Regulation of Biliary Function

Summary

Principal Investigator: GIANFRANCO D ALPINI
Affiliation: Texas A and M University
Country: USA
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

Top Publications

  1. pmc FXR-induced secretion of FGF15/19 inhibits CYP27 expression in cholangiocytes through p38 kinase pathway
    Dongju Jung
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA
    Pflugers Arch 466:1011-9. 2014
  2. pmc Epigenetic regulation of miR-34a expression in alcoholic liver injury
    Fanyin Meng
    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
  3. pmc Liver carcinogenesis: rodent models of hepatocarcinoma and cholangiocarcinoma
    Samuele De Minicis
    Department of Gastroenterology, Universita Politecnica delle Marche, Ancona, Italy
    Dig Liver Dis 45:450-9. 2013
  4. pmc GABA induces the differentiation of small into large cholangiocytes by activation of Ca(2+) /CaMK I-dependent adenylyl cyclase 8
    Romina Mancinelli
    Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, University Sapienza, Rome, Italy
    Hepatology 58:251-63. 2013
  5. pmc Neuropeptide Y inhibits biliary hyperplasia of cholestatic rats by paracrine and autocrine mechanisms
    Sharon Demorrow
    Research, Central Texas Veterans Health Care System, Temple, TX 76504, USA
    Am J Physiol Gastrointest Liver Physiol 305:G250-7. 2013
  6. pmc Recent advances in the morphological and functional heterogeneity of the biliary epithelium
    Yuyan 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
  7. pmc Recent advances in the regulation of cholangiocarcinoma growth
    Heather Francis
    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
  8. pmc Regulation of placenta growth factor by microRNA-125b in hepatocellular cancer
    Gianfranco 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
  9. pmc Melatonin inhibits cholangiocyte hyperplasia in cholestatic rats by interaction with MT1 but not MT2 melatonin receptors
    Anastasia Renzi
    Temple, TX 76504, USA
    Am J Physiol Gastrointest Liver Physiol 301:G634-43. 2011
  10. pmc Melatonin exerts by an autocrine loop antiproliferative effects in cholangiocarcinoma: its synthesis is reduced favoring cholangiocarcinoma growth
    Yuyan Han
    Division Research, Central Texas Veterans Health Care System, Tempe, USA
    Am J Physiol Gastrointest Liver Physiol 301:G623-33. 2011

Scientific Experts

  • GIANFRANCO D ALPINI
  • Shannon S Glaser
  • Marco Marzioni
  • Mario Strazzabosco
  • Heather Francis
  • Billy K C Chow
  • Sharon Demorrow
  • Eugenio Gaudio
  • Paolo Onori
  • Julie Venter
  • Romina Mancinelli
  • Fanyin Meng
  • Antonio Franchitto
  • Domenico Alvaro
  • Yuyan Han
  • Guido Carpino
  • Mellanie White
  • Yoshiyuki Ueno
  • Giammarco Fava
  • Shelley Kopriva
  • Anastasia Renzi
  • Dongju Jung
  • Kelly McDaniel
  • Samuele De Minicis
  • Allison Stokes
  • Gabriel Frampton
  • Kendal Jensen
  • Dustin Staloch
  • Fuquan Yang
  • Lola M Reid
  • Antonio Benedetti
  • Francesca Bernuzzi
  • Pietro Invernizzi
  • Rachael Turner
  • Md Kamruzzaman Munshi
  • Monique Coufal
  • Jennifer Savage
  • Ian P Y Lam
  • David D Moore
  • Wallace L McKeehan
  • Paul Webb
  • Chaofeng Yang
  • J Philippe York
  • Li Wang
  • Xuefeng Xia
  • Aijun Zhang
  • Gene D Lesage
  • David Brenner
  • Gianluca Svegliati Baroni
  • Dinorah Leyva-Illades
  • Matthew Quinn
  • Hae Yong Pae
  • Kimberley Baker
  • Tatiana Kisseleva
  • Scott Swendsen
  • Hidekazu Tsukamoto
  • Taylor Francis
  • Syeda Afroze
  • Melanie White
  • Kamruzzaman Munshi
  • Xiuping Liu
  • Haiying Zhao
  • Chang Gong Liu
  • Jingang Liu
  • Jennifer McCarra
  • Claire Barbier
  • Yunfang Wang
  • Gemma Mendel
  • Oswaldo Lozoya
  • Eliane Wauthier
  • Fanyn Meng
  • Sally Priester
  • Qing Jing
  • Ana Lleo
  • Vincenzo Cardinale
  • Candace Wise
  • Guido Torzilli
  • Leo T O Lee
  • Hueng Sik Choi
  • Trenton Horst
  • Luca Marucci
  • Ashley Kossie

Detail Information

Publications33

  1. pmc FXR-induced secretion of FGF15/19 inhibits CYP27 expression in cholangiocytes through p38 kinase pathway
    Dongju Jung
    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. ..
  2. pmc Epigenetic regulation of miR-34a expression in alcoholic liver injury
    Fanyin Meng
    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...
  3. pmc Liver carcinogenesis: rodent models of hepatocarcinoma and cholangiocarcinoma
    Samuele 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...
  4. pmc GABA induces the differentiation of small into large cholangiocytes by activation of Ca(2+) /CaMK I-dependent adenylyl cyclase 8
    Romina Mancinelli
    Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, University Sapienza, Rome, Italy
    Hepatology 58:251-63. 2013
    ..GABA-induced changes were prevented by BAPTA/AM, W7, and stable knockdown of the CaMK I gene...
  5. pmc Neuropeptide Y inhibits biliary hyperplasia of cholestatic rats by paracrine and autocrine mechanisms
    Sharon Demorrow
    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...
  6. pmc Recent advances in the morphological and functional heterogeneity of the biliary epithelium
    Yuyan 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...
  7. pmc Recent advances in the regulation of cholangiocarcinoma growth
    Heather Francis
    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...
  8. pmc Regulation of placenta growth factor by microRNA-125b in hepatocellular cancer
    Gianfranco 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)...
  9. pmc Melatonin inhibits cholangiocyte hyperplasia in cholestatic rats by interaction with MT1 but not MT2 melatonin receptors
    Anastasia Renzi
    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...
  10. pmc Melatonin exerts by an autocrine loop antiproliferative effects in cholangiocarcinoma: its synthesis is reduced favoring cholangiocarcinoma growth
    Yuyan Han
    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...
  11. pmc Inhibition of histidine decarboxylase ablates the autocrine tumorigenic effects of histamine in human cholangiocarcinoma
    Heather Francis
    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)...
  12. pmc Role of stem cell factor and granulocyte colony-stimulating factor in remodeling during liver regeneration
    Fanyin Meng
    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...
  13. pmc Histamine stimulates the proliferation of small and large cholangiocytes by activation of both IP3/Ca2+ and cAMP-dependent signaling mechanisms
    Heather L Francis
    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...
  14. pmc Autocrine regulation of biliary pathology by activated cholangiocytes
    Kendal Jensen
    Scott and White Digestive Disease Research Center, TX, USA
    Am J Physiol Gastrointest Liver Physiol 302:G473-83. 2012
    ..Because many of these molecules interact with one another throughout the progression of liver fibrosis, a model speculating their involvement in the progression of cholestatic liver disease is also presented...
  15. pmc Human hepatic stem cell and maturational liver lineage biology
    Rachael Turner
    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...
  16. pmc Regulation of biliary proliferation by neuroendocrine factors: implications for the pathogenesis of cholestatic liver diseases
    Md Kamruzzaman Munshi
    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...
  17. pmc Cholangiocyte proliferation and liver fibrosis
    Shannon S Glaser
    Department of Medicine, Scott and White and Texas A and M Health Science Center, Temple, TX 76504, USA
    Expert Rev Mol Med 11:e7. 2009
    ....
  18. pmc Endothelin inhibits cholangiocarcinoma growth by a decrease in the vascular endothelial growth factor expression
    Giammarco Fava
    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...
  19. pmc Caffeic acid phenethyl ester decreases cholangiocarcinoma growth by inhibition of NF-kappaB and induction of apoptosis
    Paolo Onori
    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...
  20. pmc Bile acids inhibit duodenal secretin expression via orphan nuclear receptor small heterodimer partner (SHP)
    Ian P Y Lam
    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...
  21. pmc Follicle-stimulating hormone increases cholangiocyte proliferation by an autocrine mechanism via cAMP-dependent phosphorylation of ERK1/2 and Elk-1
    Romina Mancinelli
    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...
  22. pmc Differentially expressed adenylyl cyclase isoforms mediate secretory functions in cholangiocyte subpopulation
    Mario 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...
  23. pmc H3 histamine receptor-mediated activation of protein kinase Calpha inhibits the growth of cholangiocarcinoma in vitro and in vivo
    Heather Francis
    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...
  24. pmc Vascular factors, angiogenesis and biliary tract disease
    Shannon 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
    ....
  25. pmc Recent advances in the regulation of cholangiocyte proliferation and function during extrahepatic cholestasis
    Shannon 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
    ....
  26. pmc 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 phenotypes
    Romina 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...
  27. pmc Taurocholic acid prevents biliary damage induced by hepatic artery ligation in cholestatic rats
    Shannon Glaser
    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...
  28. pmc Differential transcriptional characteristics of small and large biliary epithelial cells derived from small and large bile ducts
    S Glaser
    Scott and White Digestive Disease Research Center, Temple, Texas, USA
    Am J Physiol Gastrointest Liver Physiol 299:G769-77. 2010
    ....
  29. pmc Neuropeptide Y inhibits cholangiocarcinoma cell growth and invasion
    Sharon Demorrow
    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...
  30. pmc 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 1
    Gianfranco 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...
  31. pmc Exendin-4, a glucagon-like peptide 1 receptor agonist, protects cholangiocytes from apoptosis
    M 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...