The design and characterisation of chemically stable and selective synthetic retinoids.

维甲酸(RA)及其天然和合成的衍生物，通常被称为维甲酸，通过调控细胞核内的转录调控，控制脊索动物的广泛细胞过程，包括分化、增殖、凋亡和动态平衡。维甲酸是一类核受体蛋白--维甲酸受体(RARs)和维甲酸X受体(RXRs)的高亲和力配体。一旦与这些受体结合，二聚化就允许形成活跃的异源二聚体(RAR/RXR)，这些异二聚体能够结合它们的目标DNA序列并启动转录。为了到达细胞核，高度亲脂的维甲酸与载体蛋白--细胞维甲酸结合蛋白(CRABPII)结合。有趣的是，CRABPII还与Cyclin D3结合，Cyclin D3是Cyclin依赖蛋白激酶(CDK)的关键调节者之一，而CDK反过来又调节所有真核细胞的细胞周期。该项目的总体目标是开发一套完整的合成维甲酸工具箱，这些工具箱针对每种类型的CRABP和RAR家族的每个成员，可用于从药物发现到细胞生物学中的荧光探针等各种应用。将使用广泛的生化、生物物理和结构工具来表征蛋白质-配体的相互作用。

Retinoid acid (RA) and its natural and synthetic derivatives, often called retinoids, control a wide range of cellular processes in chordates, including differentiation, proliferation, apoptosis and homeostasis, by regulating transcriptional control in the cell nucleus. Retinoids are high affinity ligands for a family of nuclear receptor proteins - retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Once bound to these receptors, dimerization allows the formation if activeve heterodimers (RAR/RXR) that are able to bind their target DNA sequences and initiate transcription. In order to reach the nucleus, the highly lipophilic retinoids are bound to a carrier protein, the Cellular Retinoic Acid Binding Protein (CRABPII). Intriguingly, CRABPII also binds to Cyclin D3, one of the key regulators of Cyclin Dependent Kinases (CDKs) that in turn regulate the cell cycles in all eukaryotic cells. The overall goal of this project is to develop an entire tool box of synthetic retinoids that are specific for each type of CRABP, and each member of the RAR family that can be used for application ranging from drug discovery to fluorescent probes in cell biology. The protein-ligand interaction will be characterized using a wide range of biochemical, biophysical and structural tools.