Project: Research project

Project Details


DESCRIPTION: (Adapted from the applicant's abstract) - In epidermal
keratinocytes the balance between proliferation and differentiation must be
critically regulated in order to maintain the function of the skin as a
protective barrier. Deregulation can lead to conditions such as skin cancer
and psoriasis, a skin disorder characterized by hyperproliferation and
abnormal differentiation. An understanding of the mechanisms involved in
regulating normal growth and differentiation, as well as the alterations
which lead to particular pathologic states, is important for developing
better therapies for these conditions. 1,25-dihydroxyvitamin D3 is known to
promote the differentiation of epidermal keratinocytes both in vitro and in
vivo, and this compound and/or its analogs have been used successfully to
treat psoriasis. However, the mechanism(s) through which
1,25-dihydroxyvitamin D3 exerts its effects are unclear. The investigators'
recent data indicate that 1,25-dihydroxyvitamin D3 regulates the activity
and expression of an isoform of PLD. PLD hydrolyzes membrane phospholipids
to yield phosphatidic acid, which can, in turn, be dephosphorylated to
generate diacylglycerol (DAG). Moreover, evidence from their laboratory and
others suggests that this enzyme inhibits keratinocyte growth and promotes
differentiation. Therefore, they hypothesize that PLD, via its production
of phosphatidic acid and/or DAG, mediates the prodifferentiative effects of
1,25-dihydroxyvitamin D3. This proposal seeks to define the role of PLD and
its lipid products in the 1,25-dihydroxyvitamin D3-mediated regulation of
epidermal keratinocyte growth and differentiation. To accomplish this goal
they will seek to answer several questions: 1) Does PLD activation and
expression in response to 1,25-dihydroxyvitamin D3 or its structural analogs
correlate with their ability to induce differentiation? As a corollary to
this question, the association between keratinocyte differentiation and PLD
activation and expression will also be determined. 2) Do PLD and the
products of its action mediate the prodifferentiative effects of
1,25-dihydroxyvitamin D3? In these studies the roles of PLD, PLD-derived
DAG and phosphatidic acid and PKC activity in 1,25-dihydroxyvitamin
D3-induced differentiation will be defined. The data obtained from the
proposed studies should provide critical information on the involvement of
the PLD signaling system in regulating epidermal keratinocyte growth and
differentiation and may suggest a new approach for the development of
therapeutic agents for the treatment of psoriasis and basal and squamous
StatusNot started


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