雙特異性磷酸酶12(dusp12)在治療心肌肥厚中的功能及應(yīng)用
【專利說明】雙特異性磯酸酶12 (DUSP12)在治療心肌肥厚中的功能及 應(yīng)用
[0001]
技術(shù)領(lǐng)域
[0002] 本發(fā)明屬于基因的功能與應(yīng)用領(lǐng)域,特別設(shè)及一種雙特異性憐酸酶12 (DUSP12) 在治療屯、肌肥厚中的功能及應(yīng)用。
【背景技術(shù)】
[0003] 屯、肌肥厚是屯、肌對(duì)長期生物力學(xué)壓力或容積負(fù)荷增加的代償性反應(yīng),常見于高血 壓、主動(dòng)脈瓣狹窄等屯、血管疾病,其主要表現(xiàn)為屯、肌細(xì)胞體積增大、蛋白合成增多、細(xì)胞外 基質(zhì)增多等特征[1-3]。高血壓、老年退行性主動(dòng)脈瓣疾病在我國呈逐年上升趨勢(shì)。由高血 壓等疾病所致的屯、肌肥厚、高血壓屯、臟病發(fā)病率也隨之增加。盡管屯、肌肥厚最初可W使屯、 肌細(xì)胞增大,屯、肌收縮力加強(qiáng),是一種維持正常屯、輸出量的代償機(jī)制,但長期持續(xù)性的壓力 或容積負(fù)荷過重則會(huì)引起屯、肌重構(gòu),同時(shí)由于屯、肌需氧量增大,而冠狀動(dòng)脈血供相對(duì)不足, 弓植屯、肌缺血、屯、肌細(xì)胞調(diào)亡,進(jìn)而導(dǎo)致失代償,從而引起屯、力衰竭、惡性屯、律失常、甚至巧 死等[4, 5]。研究表明隨著屯、臟左室肥厚的發(fā)生發(fā)展,屯、肌缺血、室性屯、律失常、屯、力衰竭、 巧死等屯、血管事件的發(fā)生率增加了 6~10倍[6]。
[0004] 目前認(rèn)為屯、肌肥厚是一種多種因素參與調(diào)節(jié)的復(fù)雜的動(dòng)態(tài)過程。研究發(fā)現(xiàn)長期的 生物力學(xué)壓力和/或容積負(fù)荷過度,使屯、室壁應(yīng)力增加,導(dǎo)致屯、肌肥厚。此外,血管緊張素 II(AngII)、內(nèi)皮素(ET)、兒茶酪胺、轉(zhuǎn)化生長因子-P(TGF-P)等各種胞外刺激信號(hào)可 誘導(dǎo)核內(nèi)基因表達(dá)的改變,從而導(dǎo)致屯、肌細(xì)胞肥大[7-11]。從分子水平上看屯、肌肥厚的病 變過程分=個(gè)環(huán)節(jié):胞外肥厚刺激信號(hào)的出現(xiàn)、胞內(nèi)信號(hào)轉(zhuǎn)導(dǎo)及核內(nèi)基因轉(zhuǎn)錄活化,最終誘 發(fā)細(xì)胞發(fā)生肥大表型變化。目前研究已經(jīng)顯示多種信號(hào)通路參與屯、肌肥厚的過程。其中, 巧調(diào)神經(jīng)憐酸酶calcineurin/NFAT、絲裂原活化蛋白激酶(MAPK)與PI3K/Akt/GSK3P信號(hào) 轉(zhuǎn)導(dǎo)通路W及由運(yùn)S條通路所調(diào)節(jié)的下游轉(zhuǎn)錄因子MCIP1. 4、NF-KB、AP-1、MEF2、mTOR等 在屯、肌肥厚的發(fā)生發(fā)展中起著重要作用[1,2,12-17]。巧調(diào)神經(jīng)憐酸酶(calcineurin)是 一種受巧離子及巧調(diào)素調(diào)節(jié)的多功能信號(hào)酶,可通過使活化T細(xì)胞核因子(nuclearfactor ofactivatedTcells,NFAT)轉(zhuǎn)位入核,調(diào)節(jié)核內(nèi)肥大基因(ANP、BNP)的表達(dá)[18, 19]。 MAPK包括S個(gè)亞家族巧0] :E服s、JNKs和P38-MAPK。憐酸化的MAPKs激活促進(jìn)與屯、肌肥厚 有關(guān)的下游轉(zhuǎn)錄因子NF-KB、AP-1、MEF2、NFAT等的轉(zhuǎn)錄活性,而調(diào)節(jié)細(xì)胞基因轉(zhuǎn)錄和蛋白 合成,引起屯、肌細(xì)胞肥大,導(dǎo)致屯、肌肥厚巧0]。
[0005] 雙特異性憐酸酶12 (DUSP12),是1999年發(fā)現(xiàn)的非典型DUSP家族成員之一,其基 因定位于1號(hào)染色體長臂,編碼含有340個(gè)氨基酸的蛋白質(zhì),DUSP12蛋白在成人各主要臟 器中均有表達(dá),其中在膜腺、大腦、肺臟中表達(dá)最高,在屯、臟中有中等量的表達(dá)巧1]。其細(xì) 胞內(nèi)定位目前仍有爭(zhēng)議,在不同的細(xì)胞或組織中可分別定位于細(xì)胞漿或細(xì)胞核內(nèi)。目前關(guān) 于DUSP12的相關(guān)研究仍較少,主要集中在其與糖代謝及細(xì)胞死亡的關(guān)系上。在肝細(xì)胞中, DUSP12可通過使葡萄糖激酶去憐酸化激活,從而促進(jìn)糖酵解及糖的有氧氧化巧2]。在酵 母、化la細(xì)胞、肥K293細(xì)胞中,人們發(fā)現(xiàn)其可抑制各種刺激導(dǎo)致的細(xì)胞死亡,但對(duì)細(xì)胞的增 殖沒有影響巧3]。另外在酵母中DUSP12可使酵母MAPK通路蛋白化T2去憐酸化失活巧4]。 但DUSP12在屯、臟疾病中目前仍沒有研究。
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