The objective of the study is to demonstrate that serotonin receptor agonists (1A and 1B), nerve growth factor (NGF) and vascular endothelial growth factor (VEGF) regulate (by an autocrine mechanism) the balance between proliferation/apoptosis in bile duct ligated (BDL) rats by calcium and cAMP dependent changes in the Src/ Ras/Raf/MAPK pathway. This hypothesis is based upon: 1. Cholangiocytes express the serotonin 1A and 1B, neurotrophin, and VEGF receptors, VEGFR-2 and VEGFR-3; 2. Cholangiocytes secrete serotonin, NGF and VEGF; 3. Cross-talk between intracellular calcium and adenylyl cyclase (regulated by serotonin, NGF and VEGF) exists in cholangiocytes; 4. Administration of serotonin 1A and 1B agonists to BDL rats decreases ductal mass and activates apoptosis; 5. Administration of anti-NGF antibody inhibits cholangiocyte growth and activates apoptosis, 6. Administration of anti-VEGF antibody to BDL rats blocks cholangiocyte proliferation and activates apoptosis, and 7. Serotonin, NGF and VEGF regulation of cholangiocyte growth is modulated by the calcium and cAMP dependent changes in the PKA/Src/Ras/Raf/ MAPK pathway. Consistent with the concept that VEGF (secreted by Cholangiocytes) stimulates ductal proliferation, ligation of the hepatic artery induces a decrease in VEGF expression and cholangiocyte proliferation and an increase in apoptosis, whereas administration of VEGF to rats with hepatic artery ligation prevents the effects of hepatic artery ligation on VEGF expression and cholangiocyte proliferation/loss. The applicant proposes: (i) To demonstrate that activation of serotonin type I receptors inhibits cholangiocyte proliferation in BDL rats through calcium-dependent inhibition of the cAMP/PKA/ Src/Ras/Raf/B-Raf/MAPK pathway; (ii) To evaluate the role and mechanisms of action by which nerve growth factor regulates cholangiocyte proliferation and fibrosis; and (iii) To demonstrate that cholangiocytes secrete VEGF and regulate their own ductal mass (by a balance between proliferation and apoptosis) in BDL rats through an autocrine mechanism by modulating the secretion of VEGF. The studies raise the possibility that modulation of cholangiocyte serotonin, NGF and VEGF secretion may represent a new therapeutic approach for manipulating cholangiocyte growth/loss in liver diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062975-03
Application #
7268972
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Serrano, Jose
Project Start
2005-08-01
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
3
Fiscal Year
2007
Total Cost
$197,283
Indirect Cost
Name
Texas A&M University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845
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Zhou, Tianhao; Wu, Nan; Meng, Fanyin et al. (2018) Knockout of secretin receptor reduces biliary damage and liver fibrosis in Mdr2-/- mice by diminishing senescence of cholangiocytes. Lab Invest 98:1449-1464
Sato, Keisaku; Meng, Fanyin; Giang, Thao et al. (2018) Mechanisms of cholangiocyte responses to injury. Biochim Biophys Acta Mol Basis Dis 1864:1262-1269
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Hall, Chad; Ehrlich, Laurent; Meng, Fanyin et al. (2017) Inhibition of microRNA-24 increases liver fibrosis by enhanced menin expression in Mdr2-/- mice. J Surg Res 217:160-169
Wu, Nan; Nguyen, Quy; Wan, Ying et al. (2017) The Hippo signaling functions through the Notch signaling to regulate intrahepatic bile duct development in mammals. Lab Invest 97:843-853
Wan, Ying; McDaniel, Kelly; Wu, Nan et al. (2017) Regulation of Cellular Senescence by miR-34a in Alcoholic Liver Injury. Am J Pathol 187:2788-2798

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