Identifying novel PPAR? ligands from cerebellum

尽管过氧化体增殖物激活受体β或δ(PPARβ)的经典作用是调节基因 参与脂肪酸合成的PPARβ在中枢神经系统中高表达，并参与许多大脑 功能包括髓鞘形成。作为核激素受体，PPARβ需要配体(S)才能激活 和核移位。尽管存在许多pparβ的合成配体，但对其结构尚不清楚。 脑内内源性配体对PPARβ的生理激活作用因此，我们确定了三个 可能的生理配体[1，3-二叔丁基苯(DBB)；2，4-二叔丁基苯酚(DBP)；十六酸 从小鼠小脑核提取液中提取PPARβ的甲酯。在这里，通过在硅胶中使用 相互作用研究、时间分辨FRET分析、热位移分析、定点突变和质量 光谱，我们将用PPARβ来表征这些生理分子是否是真正的配体。 此外，我们想要检查这些小脑配体是否通过 PPARβ.这项赠款提案的积极结果将突出发现新的小脑配体 PPARβ，使我们能够在未来开发基于小脑的药物来促进脑内髓鞘再生 脱髓鞘障碍。

Although the classical role of peroxisome proliferator-activated receptor β or δ (PPARβ) is to regulate genes involved in fatty acid synthesis, PPARβ is highly expressed in the CNS and it participates in many brain functions including myelination. Being a nuclear hormone receptor, PPARβ needs ligand(s) for its activation and nuclear translocation. Although there are many synthetic ligands of PPARβ, nothing is known about the physiological activation of PPARβ by endogenous ligands in the brain. Therefore, we have identified three possible physiological ligands [1,3-di-tert-butylbenzene (DBB); 2,4-di-tert-butylphenol (DBP); hexadecanoic acid, methyl ester (HAM)] of PPARβ from nuclear extracts of mouse cerebellum. Here, by using in silico interaction studies, time-resolved FRET analyses, thermal shift assay, site-directed mutagenesis, and mass spectrometry, we will characterize whether these physiological molecules are true ligands with PPARβ. Furthermore, we would like to examine whether these cerebellar ligands exhibit promyelinating effect via PPARβ. A positive outcome of this grant proposal will highlight the discovery of novel cerebellar ligands of PPARβ, allowing us to develop cerebellum-based drugs in the future to promote remyelination in demyelinating disorders.