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

基本信息

批准号：
8554750
负责人：
Mary Kathryn Doud
金额：
$ 4.22万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8554750
关键词：
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole 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 cancer therapy 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 transcription factor tumor tumor growth tumorigenesis

项目摘要

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，它通过激活两个转录因子的能力来调节多个基因的表达来发挥作用：RAR和PPARDELTA。但是，它作为治疗剂的效用受到某些肿瘤中获得的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增加。调节这两种相对途径之间RA分配的关键在于，将RA传递到各自的转录因子的两种蛋白质：CrabP-II（将RA转换为RAR）和FABP5的CrabP-II和将其运送到Ppardelta的FabP5。因此，表达高水平FABP5的细胞对RA诱导的生长抑制具有抗性，而对RA的响应显示出增强的增殖。这项工作的目的是使用天然存在的类维生素类和脂肪酸作为探针进一步研究RAR和PPARDELTA之间的这种分区。此外，该项目旨在开发用于FABP5的小分子抑制剂，该抑制剂最终可以产生一类新型的抗癌分子以与RA协同作用。