Liver disease in CF: CFTR controls innate immunity in biliary epithelium

Summary

Principal Investigator: Mario Strazzabosco
Abstract: DESCRIPTION (provided by applicant): Cystic Fibrosis (CF) is a common and clinically severe genetic disease, caused by mutations in CFTR, a membrane protein that mediates Cl- and fluid secretion in a number of secretory epithelia, including the biliary tree. About 30% of CF patients present biochemical liver abnormalities and about 10% of these develop clinically significant liver disease and hepatobiliary complications characterized by a chronic cholangiopathy that can eventually evolve into sclerosing cholangitis and focal biliary cirrhosis. Cystic Fibrosis liver disease (CFLD) negatively impacts the quality of life and survival of CF patients, and may require liver transplantation, however, the pathogenesis of this condition is not well understood. In Cftr-KO mice, bile flow and biliary secretion are reduced;however the spontaneous development of CFLD is extremely rare, suggesting that genetic and/or acquired factors other than cholestasis are at play. It has been shown that portal endotoxemia, induced by oral administration of dextrans specifically causes biliary damage in Cftr-KO mice, but not in their wild type littermates4. Using this experimental model, we recently showed that biliary damage and inflammation caused by treatment with DSS in Cftr-KO mice were not prevented by restoring biliary secretion with nor-UDCA, and that, exposure of cultured CFTR-defective cholangiocytes to LPS in vitro, significantly increased cytokine secretion and NF-?B activity as compared to WT cells. The increased activation of NF-?B was prevented by inhibition of TLR4. We also found that the activity of Src, a tyrosine kinase involved in cell response to LPS, was upregulated in CF cells and resulted in an increased phosphorylation of TLR4. We propose that Src is the potential molecular link between CFTR and TLRs. In fact, treatment with Src inhibitor PP2 blocked TLR4 phosphorylation and NF-?B activation in response to LPS. We have also found that the expression and distribution of Csk and EBP-50, involved in Src regulation, were altered in Cftr-KO cholangiocytes. In this application, we will further investigate this novel paradigm shifting hypothesis, and in particular we will elucidate 1) the pathogenetic role of different TLRs in CFLD, 2) the role of Src in linking CFTR and TLR- mediated signaling and 3) the therapeutic value of PPAR? agonist as a strategy to inhibit the TLR/NF-?B pathway in CF cholangiocytes. These studies will be performed in Cftr-defective mice and in ferrets, a novel CF model that spontaneously develops CFLD. These studies will change our current understanding of the pathogenesis and treatment of CF-cholangiopathy. Furthermore, better knowledge of the regulation of TLR pathways in the biliary epithelium, will also provide important insights into the pathogenesis of other inflammation-mediated diseases of the epithelium, providing a firm foundation for future studies in the broader field of epithelial immunology.
Funding Period: 2013-05-01 - 2018-03-31
more information: NIH RePORT

Research Grants

  1. Autocrine/Paracrine Regulation of Intrahepatic Bile Duct Growth
    GIANFRANCO D ALPINI; Fiscal Year: 2013
  2. GENE THERAPY FOR HEMOPHILIA
    Katherine A High; Fiscal Year: 2013
  3. UAB Nutrition Obesity Research Center (NORC)
    David B Allison; Fiscal Year: 2013
  4. Translational Research Center for Expedite Novel Therapies in Cystic Fibrosis
    Bonnie W Ramsey; Fiscal Year: 2013
  5. Immunologic dysfunction in biliary atresia
    Jorge A Bezerra; Fiscal Year: 2013
  6. Histamine modulation of biliary proliferation and damage
    Heather L Francis; Fiscal Year: 2013
  7. Center for Reproductive Science and Medicine
    Pamela L Mellon; Fiscal Year: 2013
  8. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
  9. Center for Gene Therapy of Cystic Firbosis
    John F Engelhardt; Fiscal Year: 2013
  10. The Molecular Determinants of Virus Induced Biliary Atresia
    Gregory M Tiao; Fiscal Year: 2013

Detail Information

Research Grants30

  1. Autocrine/Paracrine Regulation of Intrahepatic Bile Duct Growth
    GIANFRANCO D ALPINI; Fiscal Year: 2013
    ....
  2. GENE THERAPY FOR HEMOPHILIA
    Katherine A High; Fiscal Year: 2013
    ..The projects are highly interactive, and all three take full advantage of the proposed cores. ..
  3. UAB Nutrition Obesity Research Center (NORC)
    David B Allison; Fiscal Year: 2013
    ..Backed by exceptional institutional support and academic infrastructure, we request renewed funding to continue our contributions to this important area of research...
  4. Translational Research Center for Expedite Novel Therapies in Cystic Fibrosis
    Bonnie W Ramsey; Fiscal Year: 2013
    ..During the funding period, the core center will focus on development of several novel therapeutic approaches to improve overall health for patients with CF. ..
  5. Immunologic dysfunction in biliary atresia
    Jorge A Bezerra; Fiscal Year: 2013
    ..These results will identify an array of targets for new therapies that block progression of disease, restore the biliary epithelium, and foster long-term survival of patients with biliary atresia. ..
  6. Histamine modulation of biliary proliferation and damage
    Heather L Francis; Fiscal Year: 2013
    ..synthesis may be important in the inhibition of biliary hyperplasia, overexpression of HDC (leading to enhanced histamine release) may be key for stimulating biliary proliferation in ductopenic conditions associated with biliary damage ..
  7. Center for Reproductive Science and Medicine
    Pamela L Mellon; Fiscal Year: 2013
    ..The SCCPIR Human Ovary Tissue Bank provides tissue to NIH-funded investigators nation-wide. ..
  8. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
    ..These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis. ..
  9. Center for Gene Therapy of Cystic Firbosis
    John F Engelhardt; Fiscal Year: 2013
    ..These efforts have led to numerous basic and applied research findings that have enhanced the utility of gene therapies to both study and treat genetic diseases. ..
  10. The Molecular Determinants of Virus Induced Biliary Atresia
    Gregory M Tiao; Fiscal Year: 2013
    ..In so doing develop we hope to develop new treatment strategies to alter the course of this challenging disease. This project is in complete accord with the NIH mission to reduce illness and disability. ..
  11. Mechanisms of Bile Duct Morphogenesis
    Ben Z Stanger; Fiscal Year: 2013
    ..abstract_text> ..
  12. Ca2+ Waves in Hepatocytes: Mechanisms and Effects
    Michael H Nathanson; Fiscal Year: 2013
    ....
  13. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  14. Gene Networks controlling macrophage-adipocyte interactions in insulin
    Christopher K Glass; Fiscal Year: 2013
    ..abstract_text> ..
  15. Spinal Cord Injury, Plasticity and Transplant Mediated Repair
    John D Houle; Fiscal Year: 2013
    ..This Program Project has direct relevance to the design and implementation of future treatment programs for acute and delayed intervention after SCI. ..
  16. GENE AND PHARMACOLOGICAL THERAPIES FOR CYSTIC FIBROSIS
    William B Guggino; Fiscal Year: 2013
    ..Project IV will focus on the Biology of AAV. Finally, there are three cores, an Expression, a Vector Core, and an Administration Core. ..