Project 3: Molecular Targets of Rexinoid Action in Skin

项目 3：Rexinoid 在皮肤中作用的分子靶标

• 批准号: 10263924
• 负责人: Natalia Y Kedishvili
• 金额: $ 15.78万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263924
• 关键词: Agonist; All-Trans-Retinol; Anabolism; Basal cell carcinoma; Behavior; Bexarotene; Binding; Biological; Biological Assay; Carcinoma; Cell Differentiation process; Cell Proliferation; ChIP-seq; Chemoprevention; Chemopreventive Agent; Chemoprophylaxis; Cholesterol; Chronic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Cutaneous; Cyclosporine; Data; Development; Dominant-Negative Mutation; Dose; Dose-Limiting; Epidermis; Evaluation; General Population; Genes; Genetic Transcription; Growth; Headache; Hepatocyte; Hepatotoxicity; Homeostasis; Human; Hyperlipidemia; Immunocompetent; Immunocompromised Host; In Vitro; Incidence; Inflammation; Isotretinoin; Knowledge; Lead; Ligands; Liver; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Molecular; Molecular Target; Morbidity - disease rate; Mus; Musculoskeletal; Neoplasms; Oral; Organ Transplantation; Pathway interactions; Pharmaceutical Preparations; Population; Public Health; RXR; Rattus; Regulation; Retinoic Acid Receptor; Retinoids; Rodent; Serum; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Skin Carcinogenesis; Skin Carcinoma; Solid; Specificity; Squamous cell carcinoma; Symptoms; Tazarotene; Testing; Time; Tissues; Toxic effect; Transplant Recipients; Tretinoin; Triglycerides; UVB induced; Up-Regulation; analog; base; cancer biomarkers; cancer cell; cancer chemoprevention; cell type; comparative efficacy; design; drug mechanism; experimental study; genome-wide; global run on sequencing; human model; immunosuppressed; insight; keratinocyte; mammary; mouse model; next generation; novel; patient population; pleiotropism; prevent; retinoic acid receptor alpha; skin cancer prevention; skin disorder; transcriptome sequencing; uptake

PROJECT SUMMARY. The incidence of non-melanoma skin cancer is increasing worldwide and it is especially high in the solid organ transplant population. These cancers are associated with a high morbidity in this population and, thus, it represents a significant public health burden. Systemic retinoids have proven to be effective for the chemoprophylaxis of non-melanoma skin cancers. They act by activating the transcription of RXR/RAR target genes, but their exact cancer chemopreventive mechanism is still not clear because retinoids have pleiotropic effects. The major limitation to the use of synthetic RAR agonists (acitretin, isotretinoin) at the doses required for skin cancer prevention, is poor tolerance due to headaches, musculoskeletal symptoms, hyperlipidemia, mucocutaneous inflammation and hepatotoxicity. The first clinically approved RXR agonist, bexarotene, is better tolerated than retinoids. However, hyperlipidemia induced by oral bexarotene is a major problem. Drs. Muccio and Atigadda (Project 2 and Core 2) have designed a selective RXR agonist, UAB30, which effectively prevents epithelial cancers (mammary, skin, etc.) but does not increase serum triglycerides in rodents or humans. While UAB30 clearly shows promise as a safe and effective chemopreventive drug, its mechanism of action at the molecular level is poorly understood. Our preliminary data indicate that treatment with UAB30 results in increased levels of ATRA in human skin epidermis. We propose that UAB30 potentiates the transcriptional activity of existing endogenous ATRA mediated by RXR/RAR heterodimers, which induce upregulation of genes responsible for the biosynthesis of ATRA. This leads to elevated levels of ATRA and further increase in transcriptional activity of RXR/RAR heterodimers. We also propose that the amplitude of upregulation of ATRA target genes serves as a good indicator of the potency of rexinoids for chemoprevention of non-melanoma skin cancer. Finally, we propose that evaluation of the UAB30 analogs based on their ability to induce ATRA signaling in epidermis can lead to development of the next generation of rexinoids with efficacy comparable to bexarotene but without its toxicity. These hypotheses will be tested by defining the molecular targets and studying the mechanism of action of UAB30 in epidermis using the dominant-negative mutant of RXRα and metabolic assays of retinoid metabolism (Aim 1); by characterizing the effect of UAB30 on skin cancer and markers of cell differentiation and proliferation using our novel model of human squamous cell carcinoma and mouse models of squamous cell carcinoma and basal cell carcinoma developed by Dr. Athar (Core 3); and by evaluating the next generation of UAB30 analogs for their potency in upregulation of ATRA target genes relative to UAB30 and bexarotene (Aim 3). These studies will provide novel insights into the mechanism of UAB30 action in epidermis, and are critical for developing the next generation of highly effective and safe rexinoids for chemoprevention of non-melanoma skin cancers in organ transplant recipients, and potentially for other malignancies and skin diseases.

项目总结。 非黑色素瘤皮肤癌的发病率在全球范围内呈上升趋势，特别是在 器官移植人口。这些癌症与该人群的高发病率有关，因此，它 这是一个重大的公共卫生负担。全身性维甲酸已被证明对 非黑色素瘤皮肤癌的化学预防。它们通过激活RXR/RAR靶标的转录来发挥作用 基因，但其确切的癌症化学预防机制仍不清楚，因为维甲酸具有多效性 效果。使用合成RAR激动剂(阿维A、异维A酸)所需剂量的主要限制 预防皮肤癌，是由于头痛耐受性差，肌肉骨骼症状，高脂血症， 皮肤粘膜炎症和肝毒性。第一种临床批准的RXR激动剂贝沙罗汀效果更好 比维甲酸耐受性好。然而，口服贝克沙罗汀引起的高脂血症是一个主要问题。 Muccio博士和Atigadda博士(项目2和核心2)设计了一种选择性RXR激动剂UAB30，它 有效预防上皮癌(乳腺癌、皮肤癌等)但不会增加啮齿动物的血清甘油三酯 或者是人类。虽然UAB30清楚地显示出作为一种安全有效的化学预防药物的前景，但其机制 在分子水平上的作用还知之甚少。我们的初步数据表明，用UAB30治疗 导致人类皮肤表皮中ATRA水平的增加。我们认为，UAB30增强了 RXR/RAR异源二聚体介导的内源性ATRA转录活性 负责全反式维甲酸生物合成的基因上调。这会导致ATRA水平升高和 RXR/RAR异源二聚体转录活性进一步提高。我们还提出了波幅的概念。 全反式维甲酸靶基因上调是维甲酸类化合物化学预防效力的良好指标 非黑色素瘤皮肤癌。最后，我们建议根据UAB30模拟器的能力对其进行评估 在表皮中诱导ATRA信号可以导致下一代有效的类维A酸类药物的发展 与贝沙罗汀相当，但没有毒性。这些假说将通过定义分子来检验 利用UAB30的显性-负性突变体研究其在表皮中的作用机制 RXR、α和维甲酸代谢测定(目标1)；通过表征UAB30对皮肤癌的作用 和细胞分化和增殖的标志物使用我们的新的人类鳞癌模型 以及Athar博士(Core 3)建立的鳞状细胞癌和基底细胞癌小鼠模型；以及 通过评估下一代UAB30类似物在上调ATRA靶基因方面的效力 相对于UAB30和贝沙罗汀(目标3)。这些研究将为我们提供新的见解。 UAB30在表皮中的作用，对于开发下一代高效安全的 Rexinoid用于器官移植受者非黑色素瘤皮肤癌的化学预防，并可能用于 其他恶性肿瘤和皮肤病。