CYTOKINES AS REGULATORS OF HEPATIC FIBROSIS

  • Czaja, Mark J. (PI)

Project: Research project

Project Details

Description

The overall aim of this proposal is to obtain a better
understanding of the molecular mechanisms of hepatic fibrosis by
examining the effects of certain cytokines on the process of
collagen synthesis in the liver. Three general areas will be
investigated: (1) What effects do tumor necrosis factor (TNF) and
transforming growth factor-beta (TGF-beta) have on hepatic
collagen synthesis? Hepatocytes, hepatic fibroblasts, and hepatic
adipocytes treated with these two cytokines will be examined for
total collagen synthesis, steady-state mRNA levels, and
transcriptional rates for types I, III, and IV procollagen mRNA.
Ito cells (hepatic adipocytes) treated with TNF and TGF-beta will
also be specifically studied for the ability of these two substances
to affect adipocyte phenotype (and hence collagen synthesis) by
examining the expression of adipocyte-specific genes. In vivo
experiments will also be done by injecting TNF and TGF-beta into
normal animals and studying them for the existence of hepatic
fibrosis, as well as by examining animal models of fibrosis for
increased gene expression of these two cytokines. (2) How do
gamma-interferon (gamma-IFN) and corticosteroids inhibit
collagen synthesis and what are their effects in vivo? The three
hepatic cell types will be treated with gamma-IFN alone or with
gamma-IFN together with either TNF or TGF-beta to determine
the inhibitory effects of gamma-IFN on collagen production and
TNF and TGF-beta. Gamma-IFN's effects in vivo will be studied
in the fibrogenic animal models. Corticosteroids will be examined
by means of the CAT assay for the presence of a glucocorticoid-
repressor element. Steroids' inhibitory effects on TNF and TGF-
beta on cells in culture will also be delineated. (3) What cell type
produces collagen in vivo? The technique of in situ hybridization
will be used to determine the cell type(s) responsible for collagen
synthesis in normal and diseased livers. The sum of these individual experiments will enable us to expand
our knowledge of the process of hepatic fibrosis. Such
information is essential to preventing or developing a therapy for
this disease state.
StatusFinished
Effective start/end date7/1/876/30/92

Funding

  • National Institutes of Health: $90,288.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)

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