It is now appreciated that 1,25(OH)2D3 may have a multitude of physiologic and pharmacologic functions. There are a variety of tissues and cells that possess nuclear receptors for 1,25(OH)2D3. Although the exact physiologic role of these nuclear receptors are unknown at the present time, it is recognized that 1,25(OH)2D3 will inhibit the proliferation and induce terminal differentiation of some cells that possess its receptor. The skin is not only the organ responsible for the synthesis of vitamin D3, but it can also act as a target tissue for 1,25(OH)2D3. When cultured human keratinocytes are incubated with 1,25(OH)2D3 this hormone inhibits in a dose- dependent manner proliferation and induces terminal differentiation. Based upon these and other observations, 1,25(OH)2D3 and its analogs have been evaluated for the treatment of the hyperproliferative skin disease psoriasis. Several clinical trials have revealed that the topical and oral administration of 1,25(OH)2D3 and its analogs are effective for treating this skin disorder. The goal of this research program is to better understand the biochemistry and pharmacology of 1,25(OH)2D3 and its analogs on psoriatic skin. This will be accomplished by : 1) evaluating the biologic activity of 1,25(OH)2D3 in cultured psoriatic fibroblasts and keratinocytes, 2) determining the metabolism of 3H-1,25(OH)2D3 and 3H-25-OH-D3 in cultured human keratinocytes, and 3) evaluating in vivo and in vitro 1,25(OH)2D3 analogs that have selective activity on antiproliferation and differentiation as possible therapeutic modalities for treating this skin disorder.
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