本文選題：肝細(xì)胞生成素X + 肝臟再生�。� 參考：《中國(guó)人民解放軍軍事醫(yī)學(xué)科學(xué)院》2005年博士論文

【摘要】：哺乳動(dòng)物肝臟具有強(qiáng)大的再生能力,一般情況下,人的肝臟在受損后3天之內(nèi)啟動(dòng)肝再生,2-3周后肝臟功能基本恢復(fù),3-6個(gè)月后肝臟大小可恢復(fù)到與受損前一樣。而成年哺乳動(dòng)物肝細(xì)胞大部分長(zhǎng)期處于G_0期,只有當(dāng)肝臟在部分切除或受到損傷時(shí),殘余肝細(xì)胞才能進(jìn)行快速的分裂,進(jìn)而使殘余肝組織代償性增生。因此,作為一種器官、組織再生的理想模型,肝臟損傷及其再生的分子生物學(xué)機(jī)制一直是人們研究的熱點(diǎn)課題之一。我國(guó)是一個(gè)肝病大國(guó),病毒性肝炎、肝硬化與肝癌病人數(shù)在1.2億左右,因而深入肝細(xì)胞損傷與再生的分子生物學(xué)機(jī)制研究,開發(fā)治療肝損傷的藥物,具有十分重要的社會(huì)意義。 肝刺激物(hepatic stimulator substance,HSS)是一種能特異啟動(dòng)并促進(jìn)肝細(xì)胞增殖的活性物質(zhì)。近30年來(lái),國(guó)內(nèi)外學(xué)者圍繞肝再生的機(jī)制.對(duì)動(dòng)物源及人源的HSS作了大量深入的研究,對(duì)其組織來(lái)源、理化性質(zhì)、分離純化、生物學(xué)性能以及應(yīng)用前景等都有了較深入的了解,但始終未能分離得到具有生物活性的HSS純品,無(wú)法確定其分子結(jié)構(gòu),對(duì)其作用機(jī)理的研究也還有待闡明。 我們實(shí)驗(yàn)室從上世紀(jì)80年代開始致力于肝刺激物的分離純化研究,獲得了一種相對(duì)分子量在(10-30)×10~3Da之間,能特異刺激肝源細(xì)胞增殖,對(duì)CCl_4引起的肝損傷具治療作用的細(xì)胞組分,命名為人肝細(xì)胞生成素(hepatopoietin,HPO),并于1995年獲得美國(guó)專利。但由于其純度未能達(dá)到氨基酸序列測(cè)定的標(biāo)準(zhǔn),所以始終未能獲得其氨基酸序列,從而不能確定其真正的身份。在本研究中,我們采用DEAE-cellulose和Source15Q離子交換層析、聚丙烯酰胺凝膠電泳分離后割膠回收的方法從新生小牛肝臟中分離得到了三個(gè)具有體外促進(jìn)肝癌細(xì)胞增殖的蛋白質(zhì),經(jīng)多次富集后進(jìn)行Q-TOF質(zhì)譜測(cè)序,鑒定出其中之一是一個(gè)富亮氨酸的酸性核蛋白(Leucine-rich acidic nuclear protein,LANP),其同源的人源體是pp32。pp32是一個(gè)多功能的酸性核蛋白,在正常組織可自我更新的細(xì)胞和腫瘤組織中都有較高水平的表達(dá)。研究發(fā)現(xiàn)其在細(xì)胞的信號(hào)轉(zhuǎn)導(dǎo)、蛋白質(zhì)降解、細(xì)胞骨架動(dòng)力學(xué)以及形態(tài)發(fā)生等過程中都參與作用,但體外促進(jìn)肝細(xì)胞增殖方面目前沒有報(bào)道,因此我們也將次蛋白命名為HPO-X。
[Abstract]:The mammalian liver has a strong regenerative ability. In general, the liver function of the human liver can be restored to the same size as before after the liver regeneration is started within 3 to 3 weeks after injury and the liver function recovers after 3 to 6 months. However, most of the adult mammalian hepatocytes are in the G _ S _ 0 phase for a long time. Only when the liver is partially resected or damaged can the residual liver cells divide rapidly and the residual liver tissue proliferate compensatively. Therefore, as an ideal model of organ and tissue regeneration, the molecular biological mechanism of liver injury and regeneration has been one of the hot topics. China is a large country with liver diseases, the number of patients with viral hepatitis, liver cirrhosis and liver cancer is about 120 million. Therefore, it is of great social significance to study the molecular biological mechanism of liver cell damage and regeneration and to develop drugs for the treatment of liver injury. Hepatic stimulator substance1 (HSS) is a kind of active substance which can specifically initiate and promote the proliferation of hepatocytes. In the past 30 years, scholars at home and abroad have focused on the mechanism of liver regeneration. In this paper, we have made a lot of in-depth studies on HSS from animal and human sources, and have a deep understanding of its tissue origin, physicochemical properties, separation and purification, biological properties and application prospects. However, the pure HSS with biological activity can not be separated and its molecular structure can not be determined, and the mechanism of its action is still to be elucidated. Our laboratory began to study the isolation and purification of liver irritants in the 1980s, and obtained a cell component with a relative molecular weight of 10-30 脳 10~3Da, which can specifically stimulate the proliferation of hepatogenic cells and has therapeutic effect on liver injury induced by CCl_4. Human hepatopoietin was named hepatopoietin HPOA and was patented in the United States in 1995. However, its purity can not meet the standard of amino acid sequence determination, so it can not obtain its amino acid sequence, so it can not determine its true identity. In this study, three proteins were isolated from newborn calf liver by DEAE-cellulose and Source15Q ion exchange chromatography and polyacrylamide gel electrophoresis. Q-TOF mass spectrometry sequencing showed that one of the leucine-rich acidic nucleoproteins Leucine-rich acidic nuclear protein was identified as a multifunctional acidic nucleoprotein. The homologous human body was pp32.pp32, which was a multifunctional acidic nucleoprotein. There is a high level of expression in self-renewing cells and tumor tissues in normal tissues. It has been found that HPO-X is involved in signal transduction, protein degradation, cytoskeleton dynamics and morphogenesis. However, there is no report on the promotion of hepatocyte proliferation in vitro, so we also named the secondary protein HPO-X.
【學(xué)位授予單位】：中國(guó)人民解放軍軍事醫(yī)學(xué)科學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2005
【分類號(hào)】：R346

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本文編號(hào)：1857257