KERATINOCYTE ENVELOPES: PHYSIOLOGY &TOXIC MECHANISMS

  • Rice, Robert H, (PI)

Project: Research project

Project Details

Description

Keratinocytes comprise the principal cell type in stratified squamous
ephithelia (e.g., epidermis), major sites of chronic human disease. This
proposal concerns several aspects of cross-linked envelope formation, a
distinctive property of this cell type, in human and rat keratinocytes
serially cultivated with 3T3 feeder layer support. First, the biochemical
basis of envelope formation will be explored in light of our finding that
considerable transglutaminase activity is membrane bound. The interaction
of this enzyme with involucrin and other possible envelope constituents in
membrane fractions will be explored to ascertain the mechanism of envelope
cross-linking at the cell periphery. Second, our observation that culture
conditions strongly modulate envelope forming ability will be extended,
with emphasis on the actions of corticosteroids, retinoids and an
unidentified serum factor. This factor will be characterized and, if
possible, identified. We have found that keratinocytes grown under altered
culture conditions or from different epithelia are distinguishable not only
by envelope forming ability but also by toxic responses to
3-methylcholanthrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin. A third
aspect of the proposal is to examine in a systematic fashion cellular
responses to these and other model toxic agents (PCBs, nitrosamines) in
keratinocytes which exhibit intrinsic differences in regulation of envelope
formation. The long range objectives of this work are 1) to provide a
system for examining in keratinocytes the mechanisms of corticosteroid and
retinoid action and effectiveness of pharmaceutical derivatives, 2) to
improve human risk assessment in chemical testing, and 3) to provide a
better understanding of keratinocyte physiology and intrinsic divergence,
with special relevance to squamous metaplasia. In addition to culture
studies, we propose to apply our method of immunoperoxidase staining of
involucrin in paraffin embedded tissue sections to regions of squamous
metaplasia and leukoplakia. This work may aid in recognition and
differential diagnosis of neoplastic and perhaps other human keratinocyte
lesions.
StatusFinished
Effective start/end date3/1/802/28/87

Funding

  • National Institutes of Health

ASJC

  • Medicine(all)

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