Identifying novel PPARß ligands from cerebellum

识别小脑中的新型 PPARα 配体

• 批准号: 9155665
• 负责人: KALIPADA PAHAN
• 金额: $ 19.38万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9155665
• 关键词: Applications Grants; Astrocytes; Binding; Biological Assay; Brain; Cell Death; Cerebellum; Computer Simulation; Coupled; Demyelinating Diseases; Esters; Exhibits; Fatty Acids; Fluorescence Resonance Energy Transfer; Future; Genes; Health; Ligand Binding Domain; Ligands; Luciferases; Mass Spectrum Analysis; Mus; Myelin; Nuclear Extract; Nuclear Hormone Receptors; Nuclear Translocation; Oligodendroglia; Outcome; Palmitic Acids; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Physiological; Role; Site-Directed Mutagenesis; Time; Tissues; base; myelination; novel; remyelination

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.

尽管过氧化物体增生剂激活受体β或δ（PPARβ）的经典作用是调节基因 参与脂肪酸合成，PPARβ在中枢神经系统中高度表达，并且参与了许多大脑 包括髓鞘的功能。作为核马酮受体，PPARβ需要配体激活 和核易位。尽管PPARβ有许多合成配体，但对 大脑内源配体PPARβ的生理激活。因此，我们已经确定了三个 可能的物理配体[1,3-二甲基苯甲烯（DBB）; 2,4-di-tET叔丁基苯酚（DBP）;六核 小脑核提取物的PPARβ的酸，甲基酯（HAM）。在这里，在硅中使用 相互作用研究，时间分辨率分析，热移测定法，定点诱变和质量 光谱法，我们将表征这些物理分子是否是具有PPARβ的真实配体。 此外，我们想检查这些小脑配体是否通过 PPARβ。这项赠款提议的积极结果将突出发现新颖的小脑配体的发现 PPARβ，使我们将来能够开发基于小脑的药物，以促进在 脱髓鞘疾病。