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Grant of the Month | February 2021

    Home Grant of the Month Grant of the Month | February 2021

    Grant of the Month | February 2021

    By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2021 | Comments are Closed | 24 February, 2021 | 0

    PI: George Michalopoulos

    Title: Inhibition of EGF Receptor Prevents and Reverses Non-Alcoholic Fatty Liver Disease

    Description: In the last two decades, there has been an increased appreciation of a long-term threat, that of non-alcoholic fatty liver disease (NAFLD), evolving into non-alcoholic steatohepatitis (NASH), which can further advance into cirrhosis and hepatocellular carcinoma (HCC). Treatment of NAFLD and NASH is primarily through attempts at nutritional modification, often unsuccessful due to poor compliance and socioeconomic factors. There is currently no accepted single-agent pharmacologic treatment for NAFLD. The current proposal is based on findings from our work on liver regeneration, in which we discovered a unique role for EGFR for control of steatosis in replicating hepatocytes. We have now extended these studies in mice fed a high fat diet supplemented with fructose in the drinking water (“Fast Food Diet”, FFD). We found that in mice on FFD, concurrent EGFR inhibition completely prevented and eliminated any fat deposition in hepatocytes. Furthermore, EGFR inhibition reversed severe hepatocyte steatosis established after FFD feeding for 4 months. Detail analysis of the mechanisms revealed widespread effects of EGFR inhibition on multiple transcription factors related to lipid metabolism and subsequent consequences to specific enzymes associated with lipid biosynthesis and degradation. No such findings occur when signaling from the other of the two hepatocyte-mitogenic receptor tyrosine kinases, MET (the HGF receptor), was eliminated. The purpose of this proposal is to explore translational applications of this finding. This will be done by exploring effects of EGFR inhibitors established in human pharmacology. In addition, we will conduct parallel analysis between EGFR and MET signaling inhibition on their effects of NAFLD, aiming to uncover specific pathways unique to EGFR that may reveal new pharmacologic approaches more focused than the inhibition of the entire EGFR signaling with its potentially adverse complications. In parallel studies, we will also use available human NAFLD/NASH tissue material available in the Biorepository of the Pittsburgh Liver Research Center (PLRC). This material will be used under the established rules of IRB obtained by PLRC for such studies. We will explore activation of EGFR dependent pathways and will correlate with the histology of NAFLD/NASH. A serious complication of progression of NAFLD to NASH is development of fibrosis. We have uncovered EGFR-controlled signaling molecules in steatotic hepatocytes, which have been associated with activation of hepatic stellate cells and enhanced production of collagens. These also offer opportunities for selective pharmacology for fibrosis and their relevance will be assessed in the studies proposed.

    Source: National Institute of Diabetes and Digestive and Kidney Diseases

    Term: 2/3/21 – 01/31/25

    Amount: $473,996 (one year)

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    • Our Technologies
    • About Us
      • Welcome
      • Video
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      • What Is Regenerative Medicine?
      • Executive Committee
      • Contact Us
      • Clinical Site
    • Our Research
      • Focus Areas
        • Tissue Engineering and Biomaterials
        • Cellular Therapies
        • Medical Devices and Artificial Organs
        • Clinical Translation
      • Matrix
      • Centers
      • Laboratories
      • Clinical Trials
      • Initiatives
    • Media
      • Current News
      • News Archive
      • Video
      • Podcasts
      • Newsletter
      • Grant of the Month
      • Publication of the Month
      • Media Contact
      • Video Links
    • Professional Development
      • Seminar Series
      • Special Events
      • Student Interest Groups
      • CATER
      • Post-Doctoral Opportunities
      • Career Opportunities
      • Wiegand Summer Internship
      • Admissions
      • Summer School
      • 2021 Scientific Retreat
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