Novel Biosynthethic Pathway for Secosteroids and the Skin

用于 Secosteroids 和皮肤的新型生物合成途径

• 批准号: 8504632
• 负责人: ARNOLD E POSTLETHWAITE
• 金额: $ 30万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8504632
• 关键词: 7-dehydrocholesterol; 7-dehydropregnenolone; Adjustment Disorders; Adjuvant; Adrenal Glands; Anti-Inflammatory Agents; Anti-inflammatory; Basic Science; Biochemical; Biodistribution; Bioinformatics; Biological; Biological Assay; Biological Testing; Biology; Bleomycin; CYP11A1 gene; CYP27B1 gene; Calcitriol; Catalytic Domain; Cell Lineage; Cell Nucleus; Cells; Cholecalciferol; Cholesterol Monooxygenase (Side-Chain-Cleaving); Chronic; Clinical; Clinical Trials; Complement; Dermal; Development; Diffuse; Disease; Dose; Drug Kinetics; Endocrinology; Environment; Enzymes; Ergocalciferols; Fibroblasts; Fibrosis; Gene Expression; Gene Silencing; Goals; Human; Hydroxylation; Inflammatory; Ligands; Metabolic Pathway; Microarray Analysis; Molecular; Mus; Oral; Organ; Orphan; Pathway interactions; Patients; Pharmacotherapy; Phase I Clinical Trials; Placenta; Positioning Attribute; Pre-Clinical Model; Production; Property; RNA Interference; Relative (related person); Rodent; Route; Schedule; Scleroderma; Secosteroids; Serum; Side; Signal Pathway; Skin; Steroids; Technology; Testing; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Vitamin D; Vitamin D3 Receptor; analog; base; cancer therapy; clinical application; comparative efficacy; design; extracellular; in vitro activity; in vivo; keratinocyte; novel; pre-clinical; public health relevance; receptor; skin disorder; trait; ultraviolet

DESCRIPTION (provided by applicant): 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. Subaim 1 will investigate how signaling pathways in dermal fibroblasts are inhibited by 20(OH)D3 and 17,20(OH)2pD. Subaim 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. Subaim 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. Subaim 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).

描述（由申请人提供）：由P450scc调节的新的类固醇生成途径的发现代表了皮肤生物学，内分泌学和维生素D3药物治疗方面的基本和意想不到的进展。由于其高生物效力[类似于1,25(OH)2D3]而没有可识别的毒性作用，这种新型类固醇可以作为增生性、纤维化和其他皮肤病的治疗剂。它们的产量

项目成果

Pathogenesis of Systemic Sclerosis.

• DOI: 10.3389/fimmu.2015.00272
• 发表时间: 2015
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Pattanaik D;Brown M;Postlethwaite BC;Postlethwaite AE
• 通讯作者: Postlethwaite AE

Ultraviolet radiation regulates cortisol activity in a waveband-dependent manner in human skin ex vivo.

• DOI: 10.1111/bjd.12096
• 发表时间: 2013-03
• 期刊: The British journal of dermatology
• 作者: Skobowiat C;Sayre RM;Dowdy JC;Slominski AT
• 通讯作者: Slominski AT

Metabolism of 1alpha-hydroxyvitamin D3 by cytochrome P450scc to biologically active 1alpha,20-dihydroxyvitamin D3.

• DOI: 10.1016/j.jsbmb.2008.10.005
• 发表时间: 2008-12
• 期刊: JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
• 影响因子: 4.1
• 作者: Tuckey, Robert C.;Janjetovic, Zorica;Li, Wei;Nguyen, Minh N.;Zmijewski, Michal A.;Zjawiony, Jordan;Slominski, Andrzej
• 通讯作者: Slominski, Andrzej

Expression of Vitamin D Receptor (VDR) Positively Correlates with Survival of Urothelial Bladder Cancer Patients.

维生素D受体（VDR）的表达与尿路上皮膀胱癌患者的存活正相关。

• DOI: 10.3390/ijms161024369
• 发表时间: 2015-10-15
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Jóźwicki W;Brożyna AA;Siekiera J;Slominski AT
• 通讯作者: Slominski AT

Metabolism of cholesterol, vitamin D3 and 20-hydroxyvitamin D3 incorporated into phospholipid vesicles by human CYP27A1.

• DOI: 10.1016/j.jsbmb.2011.11.012
• 发表时间: 2012-04
• 期刊: JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
• 影响因子: 4.1
• 作者: Tieu, Elaine W;Li, Wei;Chen, Jianjun;Baldisseri, Donna M;Slominski, Andrzej T;Tuckey, Robert C
• 通讯作者: Tuckey, Robert C