The transcriptional regulation of the genes encoding the two type I collagen chains, alpha1(I) and alpha2(I), is one of special interest because these genes are expressed at widely different levels that correlate with the tissue specificity of collagen synthesis, and with development and maturation of the organism. Furthermore, the genes for alpha1(I) and alpha2(I) are responsive to cues generated by injury and repair, and by a variety of cytokines, hormones, and pharmacological agents. Finally, the expression of type I collagen genes is disturbed in orders such as pulmonary fibrosis and cirrhosis, and in diseases such as scleroderma. Although post-transcriptional mechanisms undoubtedly play an important role in regulating collagen synthesis, there is good evidence that transcriptional control represents the major means by which this regulation is achieved. A major goal of this grant is to determine how this astonishingly intricate pattern of expression is established and maintained,, and how it is altered during development, in response to injury, and in disease. Current studies of gene regulation generally involve the evaluation of mutations in chimeric regulatory/reporter genes in transfection and transgenic experiments. While these approaches represent necessary preliminary steps, it is our contention that definitive results can best be achieved by testing such mutations in the context of the endogenous gene. Gene targeting techniques will therefore be used to create mutations in putative regulatory regions of the Collal gene in mice, and mutant mice will be evaluated for expression of the altered allele and for phenotypic changes. In particular, the proposed experiments will test the hypothesis that modular elements in the Collal gene direct the synthesis of type I collagen selectively to tissues such as skin and bone. It is anticipated that some of the mutations created in mice will generate useful models for human disorders of these tissues, specifically some of the Ehlers-Danlos syndromes and osteoporosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR011248-34
Application #
6046130
Study Section
Pathobiochemistry Study Section (PBC)
Program Officer
Tyree, Bernadette
Project Start
1975-02-01
Project End
2005-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
34
Fiscal Year
2000
Total Cost
$269,709
Indirect Cost
Name
University of Washington
Department
Biochemistry
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Rentz, Tyler J; Poobalarahi, Felicitta; Bornstein, Paul et al. (2007) SPARC regulates processing of procollagen I and collagen fibrillogenesis in dermal fibroblasts. J Biol Chem 282:22062-71
Oganesian, Anush; Au, Sandra; Horst, Jeremy A et al. (2006) The NH2-terminal propeptide of type I procollagen acts intracellularly to modulate cell function. J Biol Chem 281:38507-18
Rahkonen, Otto; Su, Ming; Hakovirta, Harri et al. (2004) Mice with a deletion in the first intron of the Col1a1 gene develop age-dependent aortic dissection and rupture. Circ Res 94:83-90
Bornstein, Paul; Agah, Azin; Kyriakides, Themis R (2004) The role of thrombospondins 1 and 2 in the regulation of cell-matrix interactions, collagen fibril formation, and the response to injury. Int J Biochem Cell Biol 36:1115-25
Bornstein, Paul; Walsh, Vanessa; Tullis, Jennifer et al. (2002) The globular domain of the proalpha 1(I) N-propeptide is not required for secretion, processing by procollagen N-proteinase, or fibrillogenesis of type I collagen in mice. J Biol Chem 277:2605-13
Bornstein, Paul (2002) The NH(2)-terminal propeptides of fibrillar collagens: highly conserved domains with poorly understood functions. Matrix Biol 21:217-26
Hankenson, K D; Bain, S D; Kyriakides, T R et al. (2000) Increased marrow-derived osteoprogenitor cells and endosteal bone formation in mice lacking thrombospondin 2. J Bone Miner Res 15:851-62
Hormuzdi, S G; Strandjord, T P; Madtes, D K et al. (1999) Mice with a targeted intronic deletion in the Col1a1 gene respond to bleomycin-induced pulmonary fibrosis with increased expression of the mutant allele. Matrix Biol 18:287-94
Liu, X; Wu, H; Loring, J et al. (1997) Trisomy eight in ES cells is a common potential problem in gene targeting and interferes with germ line transmission. Dev Dyn 209:85-91
Bornstein, P (1996) Regulation of expression of the alpha 1 (I) collagen gene: a critical appraisal of the role of the first intron. Matrix Biol 15:3-10

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