本文選題：Nbs1 + 神經(jīng)元變性�。� 參考：《北京協(xié)和醫(yī)學院》2012年博士論文

【摘要】：在DNA損傷應激反應中,MRN復合物(由Mre11蛋白、Rad50蛋白、Nbs1蛋白共同組成)能夠識別DNA損傷位點,通過調(diào)節(jié)損傷修復通路蛋白,參與DNA損傷修復。人類NbS1基因(編碼Nbs1蛋白)突變將引起“染色體斷裂綜合癥(ni jmegen breakage syndrome, NBS)",其臨床表現(xiàn)主要包括：小顱畸形、免疫缺陷、生長發(fā)育缺陷、染色體不穩(wěn)定性以及惡性腫瘤易患性等。 為進一步研究“NBS綜合癥”患者小顱畸形的發(fā)生機制,本課題組前期研究中,通過“條件性基因敲除方法(conditional knockout)"將小鼠Nbn基因在中樞神經(jīng)系統(tǒng)(central nervous system, CNS)神經(jīng)元中特異性敲除。該小鼠模型(命名為NbnCNS-edl小鼠)的表型和人類“NBS綜合癥”患者的臨床表現(xiàn)極為相似。因此該動物模型的制備為研究“NBS綜合癥”患者小顱畸形的發(fā)生機制提供了良好的實驗基礎。我們前期研究發(fā)現(xiàn),生后早期NbnCNS-del小鼠大腦組織結(jié)構(gòu)能夠形成,但其內(nèi)神經(jīng)元出現(xiàn)明顯的退行性變；而小腦的組織結(jié)構(gòu)大部分不能形成,其內(nèi)神經(jīng)元退行性變更為嚴重。另外,我們發(fā)現(xiàn),生后早期NbnCNS-edl小鼠胼胝體以及腦干區(qū)域的有髓神經(jīng)纖維極向消失,密度顯著降低,提示Nbsl可能對髓鞘形成起一定作用。 本研究從神經(jīng)膠質(zhì)細胞對神經(jīng)元的營養(yǎng)角度,探討了生后早期NbnCNS-edl小鼠大腦皮質(zhì)神經(jīng)元及有髓神經(jīng)纖維變性的分子機制。目前研究發(fā)現(xiàn),Abn基因在小鼠CNS星形膠質(zhì)細胞中的表達下調(diào),導致神經(jīng)生長因子(nerve growth factor,NGF)以及腦源性神經(jīng)營養(yǎng)因子(brain derived neurotrophic factor,BDNF)的蛋白表達水平降低,而對神經(jīng)營養(yǎng)素-3(neurotrophin-3,NT-3)的蛋白表達水平并未產(chǎn)生影響。另外,NGF的蛋白表達水平降低并未影響受體型酪氨酸蛋白激酶A(tyrosine kinase A,TrkA)以及P75神經(jīng)營養(yǎng)素受體(P75neurotrophic receptor,P75NTR)的蛋白表達水平,但是NGF與兩種受體的親和力減弱。Nbn基因在小鼠CNS小膠質(zhì)細胞中的表達下調(diào),使小膠質(zhì)細胞的功能降低,導致白細胞介素-1(interlukin-1, IL-1)及白細胞介素-6(interlukin-6, IL-6)的分泌減少。NGF以及BDNF的分泌減少下調(diào)了大腦皮質(zhì)哺乳動物雷帕霉素靶向蛋白(mammalian rapamycin targeting protein, mTOR)以及S6核糖體蛋白(S6ribosomal protein, S6RP)的磷酸化水平,使星型膠質(zhì)細胞對皮質(zhì)神經(jīng)元及有髓神經(jīng)纖維的營養(yǎng)保護作用減弱；而IL-1及IL-6的分泌減少導致核因子κB (neuclei factor-κ B, NF-κB)的磷酸化水平降低,使小膠質(zhì)細胞對皮質(zhì)神經(jīng)元及有髓神經(jīng)纖維的炎性保護作用減弱。Nbn基因在小鼠CNS少突膠質(zhì)細胞中的表達下調(diào),抑制了髓鞘堿性蛋白(myelin sheath basic protein, MBP)以及髓鞘調(diào)控轉(zhuǎn)錄因子o1igo1的蛋白表達水平,導致髓鞘發(fā)育缺陷。神經(jīng)營養(yǎng)作用以及炎性反應的減弱參與了髓鞘發(fā)育缺陷的分子機制。 綜合上述,Nbn基因在小鼠CNS中特異性敲除導致星形膠質(zhì)細胞及小膠質(zhì)細胞對大腦皮質(zhì)神經(jīng)元及有髓神經(jīng)纖維的營養(yǎng)及炎性作用減弱,分別通過下調(diào)mTOR/S6RP、NF-κB信號轉(zhuǎn)導通路的活性,引起大腦皮質(zhì)神經(jīng)元退行性變及髓鞘形成障礙。
[Abstract]:In the DNA damage stress response, the MRN complex (composed of Mre11 protein, Rad50 protein, Nbs1 protein) can identify the DNA damage site and participate in the repair of DNA damage by regulating the damage repair pathway protein. The mutation of the human NbS1 gene (the coded Nbs1 protein) will cause "dyor body fracture syndrome (Ni jmegen breakage)". The main manifestations include small cranial deformities, immunodeficiency, growth and development defects, chromosomal instability and susceptibility to malignant tumors.
In order to further study the mechanism of small craniofacial malformation in "NBS syndrome", in our previous study, the specific knockout of the mouse Nbn gene in the central nervous system (central nervous system, CNS) neurons was carried out by the conditional gene knockout method (conditional knockout). The mouse model (named as NbnCNS-edl mouse) The phenotype is very similar to that of the human "NBS syndrome". Therefore, the preparation of this animal model provides a good experimental basis for the study of the mechanism of small craniofacial malformation in "NBS syndrome" patients. Our previous study found that the brain tissue of NbnCNS-del mice could be formed in the early postnatal period, but the neurons in it appeared in the early stage. In addition, we found that the myelinated nerve fibers in the corpus callosum and the brain stem regions disappeared and the density decreased significantly in the early NbnCNS-edl mice, suggesting that Nbsl may play a role in the formation of myelin sheath.
In this study, from the nutritional angle of neuroglia cells to neurons, the molecular mechanism of neuronal degeneration in the cerebral cortex and myelinated nerve of NbnCNS-edl mice in the early postnatal period was investigated. The present study found that the expression of Abn gene in CNS astrocytes was down regulated, leading to the nerve growth factor (NGF) and the brain source. The protein expression level of brain derived neurotrophic factor (BDNF) was reduced, but it did not affect the protein expression level of neurotrophin -3 (neurotrophin-3, NT-3). In addition, the decrease of the protein expression level of NGF did not affect the type of tyrosine protein kinase A (tyrosine kinase) and neuronutrition. The protein expression level of P75neurotrophic receptor (P75NTR), but the affinity of NGF and two receptors weakened the expression of.Nbn gene in the mouse CNS microglia, reduced the function of the microglia and resulted in the decrease of the secretion of interleukin -1 (Interlukin-1, IL-1) and interleukin -6 (Interlukin-6, IL-6). And the decrease of BDNF secretion reduced the phosphorylation level of rapamycin target protein (mammalian rapamycin targeting protein, mTOR) and S6 ribosome (S6ribosomal protein, S6RP) in the cerebral cortex mammal, which weakened the protective effect of astrocytes on cortical neurons and myelinated nerve fibers; IL-1 and IL- were reduced. The decrease in secretion of 6 resulted in a decrease in the phosphorylation level of nuclear factor kappa B (neuclei factor- kappa B, NF- kappa B). The inflammatory protective effect of microglia on cortical neurons and myelinated nerve fibers weakened the expression of.Nbn gene in the mouse CNS oligodendrocytes, and inhibited the myelin basic protein (myelin sheath basic protein). The myelin sheath regulates the protein expression level of the transcription factor o1igo1, which leads to myelin development defects. Neurotrophic effects and diminished inflammatory responses are involved in the molecular mechanism of myelin development defects.
In addition, the specific knockout of the Nbn gene in the mouse CNS leads to the weakening of the nutritional and inflammatory effects of astrocytes and microglia on the cerebral cortex and myelinated nerve fibers. By downregulating the activity of mTOR/S6RP and NF- kappa B signal transduction pathway, the degeneration of cerebral cortex neurons and the obstruction of myelin formation are caused.
【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：博士
【學位授予年份】：2012
【分類號】：R363

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