关于GABA_B受体激活上调FMRP表达的研究
发布时间：2018-11-14 14:00
【摘要】：脆性X智力障碍蛋白(FMRP)是一种RNA结合蛋白,具有调节RNA转录并进一步调节相关基因的表达的功能。FMRP的表达失调是导致脆性X染色体综合症(FXS)的主要原因,在脆性X染色体综合症患者身上表现为孤独症相关行为,社交恐惧,癫痫症状,睡眠障碍,过度兴奋状态等。γ-氨基丁酸(GABA)是中枢神经系统中的主要抑制型神经递质,其中的代谢型γ-氨基丁酸B型受体(GABABR)被报道在多种神经疾病中具有重要作用,比如癫痫等。报道显示GABAB受体激动剂巴氯芬(baclofen)能缓解Fmr1基因敲除小鼠中脆性X染色体综合症相关的表现缺陷,比如降低听源性惊厥,正常化的树突棘密度,蛋白合成正常化,氨甲基磷酸受体的内化等。但是GABAB受体和FMRP表达调控之间的信号通路并不明朗。本文旨在展示在GABAB受体激活后引起cAMP应答原件结合蛋白(CREB)磷酸化后,进一步上调FMRP蛋白表达,并且该信号通路是通过GABAB受体转激活类胰岛素生长因子1受体(IGF1-R)实现的。此外,一种GABAB受体的正向变构调节剂CGP7930,能上调小脑颗粒神经元(CGNs)中的FMRP蛋白表达。综上所述,GABAB受体在FMRP蛋白调控中具有一定作用,使GABAB受体可作为潜在的药物靶点在未来针对脆性X染色体综合症药物开发中发挥重要作用。
[Abstract]:Fragile X mental retardation protein (FMRP) is a RNA binding protein that regulates the transcription of RNA and further regulates the expression of related genes. The imbalance of FMRP expression is the main cause of (FXS) in fragile X chromosome syndrome. In patients with fragile X chromosome syndrome, autistic behavior, social fear, epileptic symptoms, sleep disorders, hyperstimulation, and so on. Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system. The metabolic 纬-aminobutyric acid B receptor (GABABR) has been reported to play an important role in many neurological diseases, such as epilepsy. It is reported that baclofen (baclofen), a GABAB receptor agonist, can alleviate the defects associated with fragile X chromosome syndrome in Fmr1 knockout mice, such as reduced audiogenic convulsion, normalized dendritic spine density, and normalization of protein synthesis. Internalization of aminomethyl phosphate receptor. However, the signaling pathway between GABAB receptor and FMRP expression regulation is unclear. The aim of this study was to demonstrate that the expression of FMRP protein was upregulated after the activation of GABAB receptor and the phosphorylation of (CREB), the original binding protein of cAMP response. Moreover, this signaling pathway is transactivated by GABAB receptor to insulin-like growth factor 1 receptor (IGF1-R). In addition, CGP7930, a forward structure modulator of GABAB receptor, can up-regulate the expression of FMRP protein in (CGNs) of cerebellar granule neurons. In conclusion, GABAB receptor plays an important role in the regulation of FMRP protein, which makes GABAB receptor play an important role in the future development of fragile X chromosome syndrome drugs as a potential drug target.
【学位授予单位】：华中科技大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R596.1
本文编号：2331360
[Abstract]:Fragile X mental retardation protein (FMRP) is a RNA binding protein that regulates the transcription of RNA and further regulates the expression of related genes. The imbalance of FMRP expression is the main cause of (FXS) in fragile X chromosome syndrome. In patients with fragile X chromosome syndrome, autistic behavior, social fear, epileptic symptoms, sleep disorders, hyperstimulation, and so on. Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system. The metabolic 纬-aminobutyric acid B receptor (GABABR) has been reported to play an important role in many neurological diseases, such as epilepsy. It is reported that baclofen (baclofen), a GABAB receptor agonist, can alleviate the defects associated with fragile X chromosome syndrome in Fmr1 knockout mice, such as reduced audiogenic convulsion, normalized dendritic spine density, and normalization of protein synthesis. Internalization of aminomethyl phosphate receptor. However, the signaling pathway between GABAB receptor and FMRP expression regulation is unclear. The aim of this study was to demonstrate that the expression of FMRP protein was upregulated after the activation of GABAB receptor and the phosphorylation of (CREB), the original binding protein of cAMP response. Moreover, this signaling pathway is transactivated by GABAB receptor to insulin-like growth factor 1 receptor (IGF1-R). In addition, CGP7930, a forward structure modulator of GABAB receptor, can up-regulate the expression of FMRP protein in (CGNs) of cerebellar granule neurons. In conclusion, GABAB receptor plays an important role in the regulation of FMRP protein, which makes GABAB receptor play an important role in the future development of fragile X chromosome syndrome drugs as a potential drug target.
【学位授予单位】：华中科技大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R596.1
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