Project: Research project

Project Details


The research proposed in this application is designed to further elucidate
the mechanisms controlling type I collagen gene expression in both normal
and transformed cells. Type I collagen is the major interstitial collagen
and is responsible for the structural integrity of most vertebrate tissues.
Alterations in collagen production occur in a variety of pathologic and
physiologic conditions, but the molecular mechanisms underlying these
changes are not fully understood.

Both in vitro and in vivo work is proposed in phase I of this study.
Initial experiments will identify DNA/protein interactions in regulatory
regions of the alpha 1(I) collagen gene. Sequence elements mediating these
interactions will be identified and specific mutations created by
site-directed mutagenesis; the resultant change in expression of the alpha
1(I) gene will be assessed by transfection or in vitro transcription.
trans-acting factors which bind to regulatory sequences in the alpha 1(I)
gene will be identified and their role in regulating transcription or
stability of the alpha 1(I) gene characterized. The functions of these
cis-elements and trans-acting factors will then be assayed under conditions
in which the alpha 1(I) gene is known to be transcriptionally or
posttranscriptionally downregulated. Concurrently, two specific questions
will be examined in vivo using a transgenic mouse model: 1) what are the
minimal sequence elements necessary for tissue-specific expression of the
human alpha 1(I) collagen gene, and 2) what role do intronic sequences play
in regulating alpha 1(I) transcription in vivo?

In phase II, the role of various oncogenes in regulating alpha 1(I) gene
expression will be explored in detail. DNA/protein interactions in
regulatory regions of the alpha 1(I) gene will be studied before and after
transformation by different oncogenes. It is hoped that these studies will
not only broaden our understanding of collagen gene regulation, but also
further elucidate the mechanisms by which a single transforming gene can
effect the dramatic changes in cellular phenotype associated with malignant
StatusNot started


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