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

【摘要】：在DNA損傷應(yīng)激反應(yīng)中,MRN復(fù)合物(由Mre11蛋白、Rad50蛋白、Nbs1蛋白共同組成)能夠識(shí)別DNA損傷位點(diǎn),通過調(diào)節(jié)損傷修復(fù)通路蛋白,參與DNA損傷修復(fù)。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(zhǎng)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(jìn)一步研究“NBS綜合癥”患者小顱畸形的發(fā)生機(jī)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(dòng)物模型的制備為研究“NBS綜合癥”患者小顱畸形的發(fā)生機(jī)制提供了良好的實(shí)驗(yàn)基礎(chǔ)。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(yán)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(duì)髓鞘形成起一定作用。 本研究從神經(jīng)膠質(zhì)細(xì)胞對(duì)神經(jīng)元的營(yíng)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(jī)制。目前研究發(fā)現(xiàn),Abn基因在小鼠CNS星形膠質(zhì)細(xì)胞中的表達(dá)下調(diào),導(dǎo)致神經(jīng)生長(zhǎng)因子(nerve growth factor,NGF)以及腦源性神經(jīng)營(yíng)養(yǎng)因子(brain derived neurotrophic factor,BDNF)的蛋白表達(dá)水平降低,而對(duì)神經(jīng)營(yíng)養(yǎng)素-3(neurotrophin-3,NT-3)的蛋白表達(dá)水平并未產(chǎn)生影響。另外,NGF的蛋白表達(dá)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(yíng)養(yǎng)素受體(P75neurotrophic receptor,P75NTR)的蛋白表達(dá)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(xì)胞中的表達(dá)下調(diào),使小膠質(zhì)細(xì)胞的功能降低,導(dǎo)致白細(xì)胞介素-1(interlukin-1, IL-1)及白細(xì)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(dòng)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(xì)胞對(duì)皮質(zhì)神經(jīng)元及有髓神經(jīng)纖維的營(yíng)養(yǎng)保護(hù)作用減弱；而IL-1及IL-6的分泌減少導(dǎo)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(xì)胞對(duì)皮質(zhì)神經(jīng)元及有髓神經(jīng)纖維的炎性保護(hù)作用減弱。Nbn基因在小鼠CNS少突膠質(zhì)細(xì)胞中的表達(dá)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(dá)水平,導(dǎo)致髓鞘發(fā)育缺陷。神經(jīng)營(yíng)養(yǎng)作用以及炎性反應(yīng)的減弱參與了髓鞘發(fā)育缺陷的分子機(jī)制。 綜合上述,Nbn基因在小鼠CNS中特異性敲除導(dǎo)致星形膠質(zhì)細(xì)胞及小膠質(zhì)細(xì)胞對(duì)大腦皮質(zhì)神經(jīng)元及有髓神經(jīng)纖維的營(yíng)養(yǎng)及炎性作用減弱,分別通過下調(diào)mTOR/S6RP、NF-κB信號(hào)轉(zhuǎn)導(dǎo)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(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2012
【分類號(hào)】：R363

【相似文獻(xiàn)】

相關(guān)期刊論文 前10條

1 蘇蕓;謝澤鋒;辛崗;許燕璇;李康生;;LPS誘導(dǎo)大腦皮質(zhì)膠質(zhì)細(xì)胞自噬基因Beclin-1蛋白表達(dá)的研究[J];中國(guó)當(dāng)代醫(yī)藥;2011年24期

2 楊平;周yN;劉娟;黃大可;桂麗;汪淵;賈雪梅;;載脂蛋白E基因敲除及高脂飲食小鼠皮質(zhì)額葉區(qū)形態(tài)學(xué)及Mortalin表達(dá)的變化[J];安徽醫(yī)科大學(xué)學(xué)報(bào);2011年07期

3 辛崗;蘇蕓;許燕璇;陳小璇;李康生;;脂多糖活化小鼠大腦小膠質(zhì)細(xì)胞后炎性細(xì)胞因子的表達(dá)[J];中國(guó)熱帶醫(yī)學(xué);2011年08期

4 辛崗;蘇蕓;許燕璇;李康生;;LPS刺激神經(jīng)膠質(zhì)細(xì)胞條件培養(yǎng)上清誘導(dǎo)神經(jīng)元凋亡[J];腦與神經(jīng)疾病雜志;2011年04期

5 ;[J];;年期

6 ;[J];;年期

7 ;[J];;年期

8 ;[J];;年期

9 ;[J];;年期

10 ;[J];;年期

相關(guān)會(huì)議論文 前4條

1 肖榮;喬健天;閆秀珍;王瑞;;亞硒酸鈉對(duì)體外培養(yǎng)皮質(zhì)神經(jīng)元的致凋亡及相關(guān)基因的調(diào)控作用[A];中國(guó)營(yíng)養(yǎng)學(xué)會(huì)第四屆老年?duì)I養(yǎng)學(xué)術(shù)會(huì)議論文摘要匯編[C];1999年

2 周厚綸;劉慶瑩;魏瑛;蔡秋云;朱長(zhǎng)庚;;海豹油對(duì)幼年小鼠腦內(nèi)ACh、synaptophysin陽(yáng)性神經(jīng)元、GFAP陽(yáng)性細(xì)胞的影響[A];解剖學(xué)雜志——中國(guó)解剖學(xué)會(huì)2002年年會(huì)文摘匯編[C];2002年

3 蔣建清;;Ti-Al-C-N高硬度復(fù)合薄膜的研究[A];2010年海峽兩岸功能性復(fù)合材料論壇論文集[C];2010年

4 陳耀民;趙永波;;二甲雙胍對(duì)BACE1轉(zhuǎn)錄調(diào)控及β淀粉樣蛋白(Aβ)生成的影響[A];2011全國(guó)老年癡呆與衰老相關(guān)疾病學(xué)術(shù)會(huì)議第三屆山東省神經(jīng)內(nèi)科醫(yī)師（學(xué)術(shù)）論壇論文匯編[C];2011年

相關(guān)博士學(xué)位論文 前5條

1 劉波;中樞神經(jīng)系統(tǒng)Nbn基因敲除小鼠大腦皮質(zhì)膠質(zhì)細(xì)胞的功能改變[D];北京協(xié)和醫(yī)學(xué)院;2012年

2 文懋;NbN、WN_x單層膜以及NbN基多層膜的微觀結(jié)構(gòu)和力學(xué)性能研究[D];吉林大學(xué);2010年

3 鄒華;Ras/Raf/ERK1/2信號(hào)通路在自閉癥發(fā)病機(jī)制中的研究[D];南方醫(yī)科大學(xué);2011年

4 李睿;NBS1缺失突變導(dǎo)致小顱畸形的分子機(jī)制研究[D];北京協(xié)和醫(yī)學(xué)院;2012年

5 吳敬波;超導(dǎo)超構(gòu)材料及亞波長(zhǎng)小孔陣列的太赫茲光譜研究[D];南京大學(xué);2012年

相關(guān)碩士學(xué)位論文 前10條

1 唐發(fā)兵;慢性乙醇中毒誘導(dǎo)小鼠大腦皮質(zhì)神經(jīng)細(xì)胞凋亡的研究[D];中國(guó)醫(yī)科大學(xué);2010年

2 劉曉宇;超導(dǎo)NbN、NbTi薄膜及其相關(guān)器件的制備研究[D];南京大學(xué);2011年

3 薛鳳英;TiN、NbN的力學(xué)性質(zhì)及TiN表面吸附CO穩(wěn)定性的第一性原理模擬與計(jì)算[D];天津師范大學(xué);2012年

4 龍志敏;丙戊酸鈉對(duì)APP/PS1雙重轉(zhuǎn)基因小鼠的神經(jīng)保護(hù)作用研究[D];重慶醫(yī)科大學(xué);2011年

5 韓睿欽;CSD在小鼠大腦皮質(zhì)中的表達(dá)及卵巢上神經(jīng)切除對(duì)雌性大鼠生殖能力的影響[D];甘肅農(nóng)業(yè)大學(xué);2011年

6 馮鵬;低水溫游泳對(duì)衰老模型小鼠腦衰老的影響[D];河北師范大學(xué);2010年

7 李美琴;Nec-1對(duì)鋁致癡呆模型認(rèn)知能力的影響及其作用機(jī)制[D];山西醫(yī)科大學(xué);2010年

8 周學(xué)超;ＶＢ過渡金屬化合物電子結(jié)構(gòu)性質(zhì)的第一性原理研究[D];南京航空航天大學(xué);2010年

9 詹從清;BRD2對(duì)小鼠大腦皮質(zhì)神經(jīng)元突起的發(fā)育調(diào)控[D];第四軍醫(yī)大學(xué);2011年

10 王琪;精確研究NbN分子電子態(tài)躍遷的P線系發(fā)射光譜[D];西華大學(xué);2012年

，

本文編號(hào)：2077975