Apoptosis and Liver Fibrogenesis

    Project: Research project

    Description

    DESCRIPTION (provided by applicant): Hepatic fibrosis is thought to be the result of a wound-healing process, marked by transforming growth factor beta (TGF- beta) production and the resulting upregulation of collagen I synthesis by stellate cells. However the relationship between chronic liver injury and fibrogenesis is not well understood. We have made several original observations regarding a possible mechanism linking chronic injury to fibrogenesis in the liver. First, we have directly demonstrated that hepatic stellate cells (HSC) are able to phagocytose apoptotic bodies of hepatocytes in vitro, and second this results in HSC activation and upregulation of TGF-beta1 and type I collagen production. Based on these preliminary data, we propose a CENTRAL HYPOTHESIS that phagocytosis of apoptotic bodies by HSC induces fibrogenesis in the liver. The SPECIFIC AIMS of this proposal will be answering two key questions generated by this hypothesis: 1. Is phagocytosis of apoptotic bodies by HSC a specific and regulated process? A) Is phagocytosis by HSC a specific receptor-mediated process? B) Is phosphatidylserine eliciting a signaling cascade leading to HSC activation? 2. What are the signaling pathways leading to TGF-beta1 and type 1 collagen upregulation? A) Is engulfment of apoptotic bodies accompanied by activation of NADPH oxidase? B) Is the activation of the MAP-kinase pathway contributing to type I collagen and TGF-beta1 generation? In summary, inhibition of apoptosis, phagocytosis of apoptotic bodies by HSC, or signaling events occurring as a result of the phagocytic process, may prove to be therapeutic strategies to inhibit liver fibrogenesis and delay or even avoid liver transplantation.
    StatusFinished
    Effective start/end date5/15/058/31/10

    Funding

    • National Institutes of Health: $124,549.00
    • National Institutes of Health: $125,629.00
    • National Institutes of Health: $124,549.00
    • National Institutes of Health: $124,549.00
    • National Institutes of Health: $49,680.00
    • National Institutes of Health: $124,389.00

    Fingerprint

    Hepatic Stellate Cells
    Phagocytosis
    Apoptosis
    Liver
    Transforming Growth Factor beta1
    Collagen Type I
    Up-Regulation
    NADPH Oxidase
    Phosphatidylserines
    Wounds and Injuries
    Transforming Growth Factor beta
    Liver Transplantation
    Wound Healing
    Hepatocytes
    Fibrosis
    Phosphotransferases
    Collagen
    Extracellular Vesicles

    ASJC

    • Medicine(all)