The discovery of new secosteroidogenic pathways, regulated by P450scc represents a fundamental and unexpected advance in skin biology, endocrinology, and pharmacotherapy of vitamin D3. The novel secosteroids can serve as therapeutic agents for proliferative, fibrosing and other skin diseases, because of their high biological potency [similar to 1,25(OH)2D3] without identifiable toxic effects. Their production by P450scc in placenta, adrenals and in epidermal keratinocytes indicates that they can be produced in vivo. In fact, we detected 20(OH)D3 in human serum. This defines them as novel endogenous bioregulators. They are at least as potent as 1,25(OH)2D3 (calcitriol) in skin cells displaying anti-proliferative, pro-differentiation and anti-inflammatory properties. Important from clinical point of view, some of the P450scc-derived compounds [20(OH)D3 or 17,20(OH)2pD] are non-toxic in rodents at, respectively, extremely high doses as 30 or 3 ?g/kg, defining them as potential therapeutic agents for fibrosing or skin hyperproliferative or inflammatory disorders, or as adjuvants in cancer therapy. To study these pathways following aims are designed: 1. Defining the mechanism of action of 20(OH)D3 and 17,20(OH)2pD in skin fibroblasts;2. Establishing novel secosteroids (20(OH)D3 and 17,20(OH)2pD) as excellent candidates for therapy of human fibrosing diseases in preclinical models of scleroderma;3. Evaluate dosing schedules and pharmacokinetics for 20(OH)D3, or 17,20(OH)2D3 by gavage that result in optimal suppression of murine scleroderma without causing toxicity.
The aim 1 will focus on the basic science and therefore will include several subaims.
Sub aim 1 will investigate how signaling pathways in dermal fibroblasts are inhibited by 20(OH)D3 and 17,20(OH)2pD.
Sub aim 2 will investigate the degree of involvement of VDR-dependent pathways activated by 20(OH)D3 and 17,20(OH)2pD on fibroblasts. These will be complemented by testing of ligand-induced VDR translocation to the nucleus and activation of VDRE transcriptional activity.
Sub aim 3 will test the involvement of ROR in fibroblasts from ROR?-/- and ROR?- /- mice with confirmation in human fibroblasts with receptors silenced by RNAi. These will be supported by biochemical and cell-based assays. Divergence and overlaps between the actions on VDR, ROR? and ROR? will be accomplished by microarray technology.
Sub aim 4 will test whether anti-fibrotic activity of novel secosteroids is potentiated by hydroxylation at C1? using CYP27B1-/- mice. These will be complemented by comparing phenotypic effects of 1,20(OH)2D3 and 1,17,20(OH)3pD with the parental compounds.
Aim 2 will test the biological efficacy of 20(OH)D3 and 17,20(OH)2pD in preclinical models of scleroderma and will compare their i. p. to oral routes of delivery.
Aim 3 is a logical continuation of aims 1 and 2 and will test their biodistribution in organ/tissue specific accumulation of the analogs and define their possible toxicity for extremely high oral doses. These are necessary for further development in Phase I clinical trials in patients with scleroderma or other fibrosing diseases, which represents our ultimate goal (clinical application).
We will define mechanisms of action and pre-clinical utilities of two leading intermediates of newly discovered metabolic pathways of enzymatic actions of CYP11A1 on vitamin D3 and 7-dehydrocholesterol. The first one is 20-hydroxyvitamin D3 and the second one is 17,20-dihydroxypregcalciferol, a product of UVB induced transformation of 17,20-dihydroxy-7-dehydropregnenolone. .
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