Scleroderma is a devastating connective tissue disease. An increase in dermal collagen synthesis is central to its pathogenesis. This increase has been linked to deficiency of the integrin collagen receptor alpha1 beta1 (a1b1) in scleroderma fibroblasts, and also to an excess of dermal transforming growth factor-beta (TGFb). Studies of normal fibroblasts suggest that integrin a1b1 senses extracellular matrix collagen and mediates feedback inhibition on collagen synthesis. It has also been shown that TGFb causes upregulation of integrin a1b1 in some cell types. The applicants therefore propose that: 1) Increased collagen deposition in scleroderma is due to lack of the normal feedback inhibition of synthesis mediated by integrin a1b1, and 2) that the reduced levels of a1b1 seen in scleroderma fibroblasts may be due to an aberrant response to TGFbeta. Studies are proposed that will enable determination of the role of integrin a1b1 in scleroderma, and which may suggest routes for pharmacologic intervention at a key step in fibrosis. The investigators have generated mice deficient in integrin a1 by gene targeting. These animals develop normally and are fertile. Fibroblasts derived from these animals show increased synthesis of collagen I mRNA compared to wild type. The applicants will examine collagen turnover in these animals by complementary in vitro and in vivo approaches. The applicants will compare collagen synthesis by a1b1-deficient and wild-type fibroblasts in monolayer culture and in 3D gels, and examine the effect on collagen synthesis of addition to these cells of a1 antibody, a1 ligands, and TGFbeta. They will examine collagen synthesis and degradation in the skin of a1b1-deficient and wild-type animals and determine whether the fibrotic effects of TGFb injection are augmented by a1 deficiency. They will isolate alterations in collagen synthesis from alterations in collagen breakdown in vivo by crossing a1-deficient mice with collagenase-resistant mice. They will thus obtain a sensitive assay for the role of a1b1 in regulating collagen synthesis in vivo. These studies will enable them to determine the role of integrin a1b1 in scleroderma and may direct them in the future to dissect the a1 signaling pathway as a target for anti-fibrotic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR044514-02
Application #
2856154
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Serrate-Sztein, Susana
Project Start
1998-01-01
Project End
2002-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037