 |
FRISC: The Faculty Research Interests Science Comparator |
|
Associate Professor of Biochemistry
Genetics and
Development
Integrative Biology
Office: (214) 648-5026
Email: hammer@utsw.swmed.edu
Research in our laboratory is directed toward investigating
the role of transforming growth- b (TGF- b )
signaling in the regulation of organ homeostasis and in the pathogenesis of fibrotic
disease. TGF- b is
the prototypic member of the TGF- b superfamily of growth factors, a diverse group of structurally
related polypeptides which are potent modulators of cell growth and differentiation. TGF- b has numerous pleiotropic
functions including inhibition of epithelial and induction of mesenchymal cell
proliferation, inhibition of mesenchymal cell differentiation and stimulation of
extracellular matrix synthesis and deposition. To address the role and importance of TGF- b signaling in regulating these
processes in vivo , we are using a targeted transgenic approach to express
components of the signaling pathway. Transgenic mice overexpressing a constitutively
active human TGF- b
gene under the control of the rat phosphoenolpyrvate carboxykinase (PEPCK) regulatory
sequence develop severe fibrosis of the liver, kidney and adipose tissue and exhibit a
near absence of body fat. Expression of the transgene in hepatocytes resulted in increased
collagen deposition, altered lobular organization, increased hepatocyte turnover, and in
extreme cases, hemorrhage and thrombosis. To definitely assign or rule out a critical role
for TGF- b signaling
in the regulation of liver homeostasis, we have generated transgenic mice expressing a
dominant-negative TGF- b type-II receptor in liver. Expression of this mutant receptor should block
signaling by all TGF- b isoforms. These animals will be used in conjunction with the ligand
overexpressing mice to assess the importance of TGF- b signaling in liver growth, regeneration and the development of
neoplasia.
Apoptosis is critically required for the maintenance of
liver homeostasis through the select removal of damaged or senescent hepatocytes. It is
now evident that certain forms of liver disease are associated with increased or decreased
apoptotic activity, resulting in either extensive hepatocyte death or increased hepatocyte
survival. We are extending our studies in liver to address the importance of functional
hepatic apoptotic pathways to liver homeostasis. We are generating lines of transgenic
mice overexpressing the anti-apoptotic baculovirus p35 protein in liver, and if hepatocyte
apoptosis is blocked, we will use these mice in combination with other established mouse
models which develop either hepatic fibrosis or hepatic hyperplasia to determine the role
of apoptosis in the pathobiology of these disorders.
A third interest of the laboratory is in studying the
molecular and cellular mechanisms by which the human class I histocompatibility gene
HLA-B27 induces an array of inflammatory disorders called the spondyloarthropathies. We
have established a transgenic rat model of HLA-B27 induced disease and are using these
animals to investigate the molecular properties of the B27 protein that induce this
disease and the mechanisms by which it occurs.
Selected Publications:
Clouthier DE, Avarbock MR, Maika SD, Hammer RE, and
Brinster RL (1996) Rat spermatogenesis in mouse testis. Nature 381: 418-421.
Shimano H, Horton JD, Hammer RE, Shimomura J, Brown MS, and
Goldstein JL (1996) Overproduction of cholesterol and fatty acids causes massive liver
enlargement in transgenic mice expressing truncated SREBP-la. J Clin Invest 98:1575-1584
Shimano H, Horton JD, Shimomura I, Hammer RE, Brown MS and
Goldstein JL (1997) Isoform 1c of sterol regulatory element binding protein is less active
than isoform 1a in livers of transgenic mice and in cultured cells. J Clin Invest 99:
846-854
McCormick SPA, Ng JK, Cham CC, Taylor S, Marcovina S,
Segrest JP, Hammer RE, and Young SG (1997) Transgenic mice expressing human apoB95 and
apoB97: evidence that sequences within the carboxyl-terminal portion of human apoB100 are
important for the assembly of lipoprotein(a). J Biol Chem. (in press)
Clouthier DE, Comerford SA, and Hammer RE (1997) Hepatic
fibrosis, glomerulonephritis and lipodystrophy-like syndrome in PEPCK-TGF b 1 transgenic mice. J Clin
Invest (submitted)
Page maintained by Stephanie Robertson
Last Updated: 17 Nov 2000
Extraction Method: Expand using Medical Synonyms-
Eliminated words list: MedlinePlus List
-
Similarity Method: Weighted keyword count
-
Database: Medline abstracts (1967 - Present)
-
Publication Type: All
-
Score Calculation Method: Cosine Similarity Method
-
Sort by: Score
-
Show: Top 100 hits
-
Results computed on: 6/9/2006