NUCLEAR RECEPTOR LIGAND TARGETING BY THE FATTY ACID BINDING PROTEINS: IMPLICATION

脂肪酸结合蛋白靶向核受体配体：意义

• 批准号: 8911790
• 负责人: Mary Kathryn Doud
• 金额: $ 4.31万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8911790
• 关键词: Affinity; Anticarcinogenic Agents; Apoptosis; Apoptotic; Behavior; Binding; Binding Proteins; Cancer Cell Growth; Cell Cycle Arrest; Cell Proliferation; Cell Survival; Cells; Chemopreventive Agent; Clinical; Data; Development; Equilibrium; Fatty Acids; Gene Expression; Genes; Goals; Growth; Hormones; Human; Inhibition of Cancer Cell Growth; Lead; Ligands; Lipid Binding; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Modeling; Nuclear Receptors; PPAR delta; Pathway interactions; Proteins; Research; Resistance; Retinoic Acid Receptor; Retinoids; Series; Signal Transduction; Stearates; Testing; Therapeutic Agents; Tretinoin; Up-Regulation; Vitamin A; Work; base; cancer cell; cell growth; cellular retinoic acid binding protein II; fatty acid-binding proteins; high throughput screening; human FABP5 protein; inhibitor/antagonist; insight; novel; oncology; pre-clinical; receptor; response; small molecule; targeted cancer therapy; transcription factor; tumor; tumor growth; tumorigenesis

Retinoic acid (RA) is a potent anticarcinogenic agent that functions by regulating the expression of multiple genes through its ability to activate two transcription factors: RAR and PPARDELTA. However, its utility as a therapeutic agent is limited by RA-resistance that is acquired in some tumors. Activation of RAR results in inhibition of cancer cell growth, while activation of PPARDELTA leads to enhanced growth and survival. The key to regulating the partitioning of RA between these two opposing pathways lies in the two proteins that deliver RA to their respective transcription factors: CRABP-II, which delivers RA to RAR, and FABP5, which transports it to PPARDELTA. Hence, cells that express a high level of FABP5 become resistant to RA-induced growth inhibition and, instead, display enhanced proliferation in response to RA. The goal of this work is to further investigate this partitioning between RAR and PPARDELTA using naturally occurring retinoids and fatty acids as probes. Moreover, this projects aims to develop a small molecule inhibitor(s) for FABP5 which could ultimately yield a novel class of anticarcinogenic molecules to synergize with RA.

视黄酸 (RA) 是一种有效的抗癌剂，通过激活两种转录因子：RAR 和 PPARDELTA，调节多个基因的表达。然而，其作为治疗剂的用途受到某些肿瘤中获得的 RA 耐药性的限制。 RAR 的激活可抑制癌细胞生长，而 PPARDELTA 的激活可增强生长和存活。调节 RA 在这两条相反途径之间分配的关键在于将 RA 传递至各自转录因子的两种蛋白质：CRABP-II（将 RA 传递至 RAR）和 FABP5（将 RA 转运至 PPARDELTA）。因此，表达高水平 FABP5 的细胞对 RA 诱导的生长抑制具有抵抗力，并且响应 RA 而表现出增强的增殖。这项工作的目标是使用天然存在的类视黄醇和脂肪酸作为探针，进一步研究 RAR 和 PPARDELTA 之间的这种分配。此外，该项目旨在开发一种 FABP5 的小分子抑制剂，最终可以产生一类与 RA 协同作用的新型抗癌分子。