Identifying novel PPARß ligands from cerebellum

虽然过氧化物酶体增殖物激活受体β或δ（过氧化物酶体增殖物激活受体β或δ）的经典作用是调节基因， 参与脂肪酸的合成，PPARβ在中枢神经系统中高度表达，并参与许多脑内 包括髓鞘形成的功能。作为一种核激素受体，PPARβ的激活需要配体的参与 和核转位。虽然有许多合成的PPARβ配体，但对PPARβ的结构和功能尚不清楚。 通过脑中的内源性配体对PPARβ的生理激活。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）;十六烷酸] 酸，甲酯（HAM）]。在这里，通过计算机模拟 相互作用研究、时间分辨FRET分析、热位移测定、定点诱变和质谱分析。 因此，我们将通过光谱分析来表征这些生理分子是否是与PPARβ的真正配体。 此外，我们还想研究这些小脑配体是否通过以下途径表现出早髓鞘化作用： 过氧化物酶体增殖物激活受体β。这项拨款提案的积极成果将突出新的小脑配体的发现， PPARβ，使我们能够在未来开发基于小脑的药物，以促进髓鞘再生。 脱髓鞘疾病

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.