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

视黄酸（Retinoic acid， RA）是一种有效的抗癌药物，它通过激活两种转录因子RAR和PPARDELTA来调节多种基因的表达。然而，它作为一种治疗剂的效用受到某些肿瘤获得的ra耐药性的限制。激活RAR可抑制癌细胞生长，而激活PPARDELTA可促进癌细胞生长和存活。调控RA在这两种相反通路之间分配的关键在于将RA传递给各自转录因子的两种蛋白：将RA传递给RAR的CRABP-II和将RA传递给PPARDELTA的FABP5。因此，表达高水平FABP5的细胞对RA诱导的生长抑制产生抗性，相反，在RA的反应中表现出增强的增殖。这项工作的目的是利用天然存在的类维生素a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，本项目旨在开发FABP5的小分子抑制剂，最终产生一类新的抗癌分子，与RA协同作用。

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.