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，其通过激活两种转录因子RAR和PPARDELTA来调节多个基因的表达。然而，其作为治疗剂的效用受到在一些肿瘤中获得的RA抗性的限制。RAR的激活导致癌细胞生长的抑制，而PPARDELTA的激活导致生长和存活的增强。调节RA在这两种相反途径之间分配的关键在于将RA递送至其各自转录因子的两种蛋白质：将RA递送至RAR的CRABP-II和将其转运至PPARDELTA的FABP 5。因此，表达高水平FABP 5的细胞变得对RA诱导的生长抑制具有抗性，并且相反，响应于RA而显示增强的增殖。这项工作的目标是进一步研究RAR和PPARDELTA之间的这种分区使用天然存在的类维生素A和脂肪酸作为探针。此外，该项目旨在开发FABP 5的小分子抑制剂，其最终可能产生一类新型抗癌分子，与RA协同作用。