One of the cardinal manifestations of Scleroderma or Systemic Sclerosis (SSc) is excessive production of connective tissue matrix which impairs function in the skin and multiple internal organs. While the pathogenic mechanisms underlying this disease are complex and incompletely understood, it is likely that many of the harmful aspects with respect to connective tissue are mediated by the manifold effects of TGF-beta acting as a final common pathway. Strong evidence suggests that many of the effects of TGF-beta on fibroblast extracellular matrix may be mediated by connective tissue growth factor (CTGF) Our preliminary data demonstrate that CTGF expression by cultured SSC and normal fibroblasts is greatly stimulated by TGF-beta1 aqnd we have confirmed the presence of excess CTGF in the dermis of SSc patients by immunolocalization. We pose the following hypotheses: (1) TGF-beta stimulation of CTGF expression requires the activity of prenylated protein(s) and protein kinase C (PKC) in addition to the Smads. (2) CTGF is a major mediator of the fibroproliferative response, exerting its activity through binding to integrin cell surface receptor(s). (3) Alteration in the regulation of CTGF expression and/or its activity is a significant feature of the pathogenic fibrotic response found in SSc. In order to test these hypotheses, we propose the following aims: (1) To identify and characterize the molecular mechanisms whereby TGF-beta stimulates expression of CTGF in normal and SSC fibroblasts. (2) To define the signaling pathways whereby CTGF increases expression of collagen in normal and SSC fibroblasts. (3) To identify and characterize CTGF cis- responsive elements in the promoter of the COLIA1 gene and their cognate transacting factors. Identification of the mechanisms of action of CTGF and the pathways regulating its expression are of considerable importance, since CTGF may play a key role in the pathogenesis of SSC and blocking its abnormal production may ameliorate the most harmful features of the fibrotic response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
James A. Shannon Director's Award (R55)
Project #
1R55AR049065-01
Application #
6659646
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Tyree, Bernadette
Project Start
2002-09-20
Project End
2004-08-31
Budget Start
2002-09-20
Budget End
2004-08-31
Support Year
1
Fiscal Year
2002
Total Cost
$100,000
Indirect Cost
Name
University of Pennsylvania
Department
Anatomy/Cell Biology
Type
Schools of Dentistry
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104