本文選題：ADAM10 + 基因條件剔除　； 參考：《復(fù)旦大學(xué)》2007年博士論文

【摘要】： Notch信號(hào)通路在哺乳動(dòng)物胸腺細(xì)胞發(fā)育過程的多個(gè)階段發(fā)揮關(guān)鍵作用。該通路的失調(diào)將導(dǎo)致T細(xì)胞淋巴瘤等疾病的發(fā)生。跨膜蛋白Notch受體與配體結(jié)合后經(jīng)過受嚴(yán)格調(diào)控的多步蛋白裂解,釋放出胞內(nèi)轉(zhuǎn)錄活性片段(IntracellularNotch,ICN),并進(jìn)入細(xì)胞核,引發(fā)Notch下游靶基因的轉(zhuǎn)錄。在果蠅中的研究表明,kuzbanian(kuz)基因編碼一個(gè)能裂解激活Notch受體的蛋白酶。因此推測(cè)在哺乳動(dòng)物中KUZ的同源蛋白ADAM10對(duì)胸腺細(xì)胞發(fā)育過程中Notch通路的激活也起重要作用。為驗(yàn)證這一推測(cè),我們利用基因打靶技術(shù),成功培育了Adam10基因條件剔除小鼠,并在小鼠胸腺細(xì)胞中特異性地剔除Adam10基因。我們發(fā)現(xiàn)Adam10基因失活導(dǎo)致小鼠胸腺明顯變小、胸腺細(xì)胞總數(shù)和雙陽性(DP)細(xì)胞數(shù)量明顯減少,這些都與以前在相同條件下剔除Notch1基因的小鼠表型相似。進(jìn)一步研究顯示,缺乏Adam10的胸腺細(xì)胞中Notch1及其下游靶基因的活化受到抑制。我們的研究表明,ADAM10在胸腺細(xì)胞發(fā)育中能通過調(diào)節(jié)Notch的裂解活化過程來調(diào)控胸腺細(xì)胞的分化與成熟。作為一種定位于細(xì)胞膜上的蛋白水解酶,ADAM10也是一個(gè)潛在的治療Notch信號(hào)失調(diào)相關(guān)疾病的藥物靶點(diǎn)。
[Abstract]:Notch signaling pathway plays a key role in multiple stages of mammalian thymocyte development. The imbalance of this pathway will lead to T cell lymphoma and other diseases. After binding to the ligand, the transmembrane protein Notch receptor cleavage through the tightly regulated multistep protein, releasing the intracellular transcriptional active fragment (ICN) and entering the nucleus to initiate the transcription of the Notch downstream target gene. Studies in Drosophila have shown that the Kuzbanian (kuz) gene encodes a protease that cleavage and activates Notch receptors. It is suggested that the KUZ homologous protein ADAM10 may also play an important role in the activation of Notch pathway during the development of thymocytes in mammals. To verify this hypothesis, we successfully culled Adam10 gene conditioned culling mice by gene targeting technique, and specifically culled Adam10 gene in mouse thymocytes. We found that inactivation of the Adam10 gene resulted in a significant decrease in the number of thymocytes and the number of double positive (DP) cells in the thymus of mice, which were similar to the phenotypes of mice that had previously eliminated the Notch1 gene under the same conditions. Further studies showed that the activation of Notch1 and its downstream target genes in thymocytes lacking Adam10 was inhibited. Our results suggest that ADAM10 can regulate the differentiation and maturation of thymocytes by regulating Notch cleavage and activation during the development of thymocytes. ADAM10, a proteolytic enzyme located on the cell membrane, is also a potential target for the treatment of Notch signaling disorders.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2007
【分類號(hào)】：R392

【相似文獻(xiàn)】

相關(guān)期刊論文 前10條

1 劉素芳;Notch信號(hào)與神經(jīng)干細(xì)胞分化[J];河南醫(yī)學(xué)研究;2004年04期

2 葉靜靜,馬道新,趙建強(qiáng),紀(jì)春巖;四種Notch配體信號(hào)功能活性比較[J];山東醫(yī)藥;2004年07期

3 魯茁壯,吳祖澤,劉紅軍,張群偉,賈向旭,王立生;人Delta-like-1胞外區(qū)在CHO細(xì)胞的表達(dá)純化及對(duì)造血祖細(xì)胞的擴(kuò)增作用[J];中國(guó)實(shí)驗(yàn)血液學(xué)雜志;2003年03期

4 王澤劍;Notch,Wnt信號(hào)通路及其與阿爾采末病的關(guān)系[J];國(guó)外醫(yī)學(xué).生理.病理科學(xué)與臨床分冊(cè);2002年05期

5 賈向旭,魯茁壯,王華,段海峰,張群偉,吳祖澤,王立生;激活Notch信號(hào)抑制多發(fā)性骨髓瘤細(xì)胞凋亡[J];中國(guó)實(shí)驗(yàn)血液學(xué)雜志;2004年03期

6 何飛,楊崢嶸,譚穎徽;Notch配體Delta1對(duì)人牙髓干細(xì)胞分化的影響[J];牙體牙髓牙周病學(xué)雜志;2005年04期

7 魯茁壯,吳祖澤,張群偉,王華,劉紅軍,賈向旭,王立生;重組人Delta-like-1胞外區(qū)促進(jìn)細(xì)胞因子對(duì)臍帶血造血祖細(xì)胞的擴(kuò)增[J];軍事醫(yī)學(xué)科學(xué)院院刊;2004年02期

8 張家墅;甄海寧;章翔;;Notch信號(hào)通路與腦腫瘤研究現(xiàn)狀[J];中華神經(jīng)外科疾病研究雜志;2008年06期

9 俞海;錢關(guān)祥;葛盛芳;;Notch途徑與宮頸癌細(xì)胞系的增殖調(diào)控[J];生命的化學(xué);2006年04期

10 付劍亮;孫曉江;;Notch信號(hào)通路與神經(jīng)系統(tǒng)疾病[J];國(guó)際神經(jīng)病學(xué)神經(jīng)外科學(xué)雜志;2007年03期

相關(guān)會(huì)議論文 前10條

1 高嵩;劉鵬;;Notch信號(hào)通路的失活損害了成骨細(xì)胞礦化的進(jìn)程[A];中華醫(yī)學(xué)會(huì)第三次骨質(zhì)疏松和骨礦鹽疾病中青年學(xué)術(shù)會(huì)議論文匯編[C];2011年

2 郭萌;張華;邊鳳花;李舸;夏國(guó)良;;在小鼠原始卵巢形成過程中孕酮能夠抑制Notch信號(hào)通路的表達(dá)[A];全國(guó)動(dòng)物生理生化第十一次學(xué)術(shù)交流會(huì)論文摘要匯編[C];2010年

3 蘭雨;;Endothelial Smad4 Maintains Cerebrovascular Integrity by Activating N-cadherin through Cooperation with Notch[A];第二屆模式生物與人類健康研討會(huì)會(huì)議論文集[C];2012年

4 史濤坪;;Association of Low Expression of Notch-1 and Jagged-1 in Human Papillary Bladder Cancer and Shorter Survival[A];第二屆中國(guó)科學(xué)院博士后學(xué)術(shù)年會(huì)暨高新技術(shù)前沿與發(fā)展學(xué)術(shù)會(huì)議程序冊(cè)[C];2010年

5 林春蘭;鄭海濤;王春燕;楊力建;陳少華;李，

本文編號(hào)：2113513