The regulatory mechanisms that control the production of type I collagen pose a challenge to biologists interested in the regulation of gene expression and to clinicians concerned with connective tissue disorders. Type I collagen represents a major secreted product of fibroblasts, osteocytes, smooth muscle cells and a host of other mesenchymal cells. There is therefore no tissue whose structural integrity is not dependent on an appropriate balance between the synthesis and degradation of this matrix component. Since we know that collagens also function in cell- matrix interactions to instruct cellular activity during morphogenesis and in tissue repair, the need for careful regulation of matrix production becomes even more clearcut. The regulation of collagen synthesis can and probably does occur at many levels during the elaboration of this complex macromolecule. Nevertheless, there is increasing evidence that transcription and related steps that influence the level of functional mRNAs for the alpha1(I) and alpha2(I) chains of type I collagen serve as major control points. Fundamentally, transcriptional control is generated by the interaction of a complex set of cis-acting regulatory elements in DNA with a corresponding set of trans-acting DNA-binding proteins. The way in which this transcription complex functions is influenced by signals generated by interactions of cytokines with cellular receptors; in the case of collagen gene expression, TGF-beta, IL-1, IL-6 and gamma-interferon appear to play important roles. This project will concern itself with a thorough characterization of the transcription complexes that serve to regulate the rate of collagen gene transcription and to achieve coordinate control of the two genes. Regulatory elements in the promoters and first introns of the human alpha1(I) and alpha2(I) collagen genes will be defined and the way in which these elements interact via transcription factors will be elucidated. The manner in which cytokines influence the function of transcription complexes will be determined. In selected cases, novel transcription factors will be purified and characterized and their genes cloned. Factors that contribute to the stability of collagen mRNAs will be examined. The nature of mutations that transcriptionally inactivate type I collagen genes and lead to the genetic disorder, osteogenesis imperfecta type I, will be elucidated. If a thorough characterization of the processes that effect transcriptional control of type I collagen genes can be achieved, it is likely that therapeutic control of collagen production can be designed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AR011248-32
Application #
2653901
Study Section
Special Emphasis Panel (NSS)
Project Start
1975-02-01
Project End
2000-01-31
Budget Start
1998-02-01
Budget End
1999-01-31
Support Year
32
Fiscal Year
1998
Total Cost
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
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
Slack, J L; Parker, M I; Bornstein, P (1995) Transcriptional repression of the alpha 1(I) collagen gene by ras is mediated in part by an intronic AP1 site. J Cell Biochem 58:380-92

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