Project 3: Molecular Targets of Rexinoid Action in Skin

项目 3：Rexinoid 在皮肤中作用的分子靶标

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要。非黑色素瘤皮肤癌的发病率在全球范围内不断增加，在实体皮肤癌中尤其高这些癌症与该人群的高发病率相关，因此，已证明，系统性维A酸对公共健康是一个重大负担。它们通过激活 RXR/RAR 靶标的转录发挥作用，对非黑色素瘤皮肤癌进行化学预防。基因，但其确切的癌症化学预防机制仍不清楚，因为类维生素A具有多效性以所需剂量使用合成 RAR 激动剂（阿维A、异维A酸）的主要限制。预防皮肤癌，因头痛、肌肉骨骼症状、高脂血症而导致的耐受性差，第一个临床批准的 RXR 激动剂贝沙罗汀效果更好。然而，口服贝沙罗汀引起的高脂血症是一个主要问题。 Muccio 和 Atigadda 博士（项目 2 和核心 2）设计了一种选择性 RXR 激动剂 UAB30，有效预防上皮癌（乳腺癌、皮肤癌等），但不会增加啮齿类动物的血清甘油三酯虽然 UAB30 明确显示出作为一种安全有效的化学预防药物的前景，但其机制却不容忽视。我们的初步数据表明，UAB30 的治疗作用在分子水平上的作用尚不清楚。导致人类皮肤表皮中 ATRA 水平增加，我们认为 UAB30 可以增强这种作用。现有内源性 ATRA 的转录活性由 RXR/RAR 异二聚体介导，从而诱导负责 ATRA 生物合成的基因上调这导致 ATRA 和 ATRA 水平升高。我们还提出 RXR/RAR 异源二聚体的转录活性进一步增加。 ATRA 靶基因的上调是类毒素化学预防效力的良好指标最后，我们建议根据 UAB30 类似物的能力对其进行评估。诱导表皮中的 ATRA 信号传导可导致下一代有效的 rexinoids 的开发与贝沙罗汀相当，但没有其毒性。这些假设将通过定义分子来检验。使用显性失活突变体靶向并研究 UAB30 在表皮中的作用机制通过表征 UAB30 对皮肤癌的影响，进行 RXRα 和类维生素A代谢测定（目标 1）；使用我们的新型人类鳞状细胞癌模型进行细胞分化和增殖标记物 Athar 博士开发的鳞状细胞癌和基底细胞癌小鼠模型（核心 3）；通过评估下一代 UAB30 类似物上调 ATRA 靶基因的效力相对于 UAB30 和贝沙罗汀（目标 3），这些研究将为机制提供新的见解。 UAB30 在表皮中发挥作用，对于开发下一代高效且安全的药物至关重要 rexinoids 用于对器官移植受者的非黑色素瘤皮肤癌进行化学预防，并有可能用于其他恶性肿瘤和皮肤病。