關于GABA_B受體激活上調(diào)FMRP表達的研究
發(fā)布時間：2018-11-14 14:00
【摘要】：脆性X智力障礙蛋白(FMRP)是一種RNA結(jié)合蛋白,具有調(diào)節(jié)RNA轉(zhuǎn)錄并進一步調(diào)節(jié)相關基因的表達的功能。FMRP的表達失調(diào)是導致脆性X染色體綜合癥(FXS)的主要原因,在脆性X染色體綜合癥患者身上表現(xiàn)為孤獨癥相關行為,社交恐懼,癲癇癥狀,睡眠障礙,過度興奮狀態(tài)等。γ-氨基丁酸(GABA)是中樞神經(jīng)系統(tǒng)中的主要抑制型神經(jīng)遞質(zhì),其中的代謝型γ-氨基丁酸B型受體(GABABR)被報道在多種神經(jīng)疾病中具有重要作用,比如癲癇等。報道顯示GABAB受體激動劑巴氯芬(baclofen)能緩解Fmr1基因敲除小鼠中脆性X染色體綜合癥相關的表現(xiàn)缺陷,比如降低聽源性驚厥,正�；臉渫患芏�,蛋白合成正�；�,氨甲基磷酸受體的內(nèi)化等。但是GABAB受體和FMRP表達調(diào)控之間的信號通路并不明朗。本文旨在展示在GABAB受體激活后引起cAMP應答原件結(jié)合蛋白(CREB)磷酸化后,進一步上調(diào)FMRP蛋白表達,并且該信號通路是通過GABAB受體轉(zhuǎn)激活類胰島素生長因子1受體(IGF1-R)實現(xiàn)的。此外,一種GABAB受體的正向變構(gòu)調(diào)節(jié)劑CGP7930,能上調(diào)小腦顆粒神經(jīng)元(CGNs)中的FMRP蛋白表達。綜上所述,GABAB受體在FMRP蛋白調(diào)控中具有一定作用,使GABAB受體可作為潛在的藥物靶點在未來針對脆性X染色體綜合癥藥物開發(fā)中發(fā)揮重要作用。
[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 緯-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.
【學位授予單位】：華中科技大學
【學位級別】：碩士
【學位授予年份】：2015
【分類號】：R596.1
本文編號：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 緯-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.
【學位授予單位】：華中科技大學
【學位級別】：碩士
【學位授予年份】：2015
【分類號】：R596.1
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