本文選題：冠脈擴(kuò)張 + 細(xì)胞外基質(zhì)��； 參考：《北京協(xié)和醫(yī)學(xué)院》2015年博士論文

【摘要】：[研究背景]隨著冠脈影像學(xué)技術(shù)的普及,冠脈擴(kuò)張(coronary artery ectasia, CAE)越來越多地被人們所認(rèn)識(shí),其發(fā)病率低但絕對(duì)人數(shù)多,且有類似于冠心病的臨床表現(xiàn),易于發(fā)生血栓事件,嚴(yán)重危害患者的健康和生命,然而目前缺乏對(duì)其針對(duì)性的治療措施,這主要是因?yàn)椴磺迤浯_切的病因和發(fā)病機(jī)制。對(duì)冠脈擴(kuò)張發(fā)病機(jī)制的深入研究,有助于科學(xué)地制定治療策略,從而緩解患者的臨床癥狀和改善長(zhǎng)期預(yù)后。[研究目的]因?yàn)楣诿}擴(kuò)張?zhí)卣餍圆±肀憩F(xiàn)為冠脈中層細(xì)胞外基質(zhì)成分的嚴(yán)重?fù)p害,我們提出假設(shè)：做為機(jī)體細(xì)胞外基質(zhì)降解的最終執(zhí)行者,蛋白酶可能在冠脈擴(kuò)張細(xì)胞外基質(zhì)的異常代謝過程中發(fā)揮著重要作用。本研究擬回答：1)冠脈擴(kuò)張細(xì)胞外基質(zhì)代謝的特點(diǎn)如何?2)蛋白酶是否和冠脈擴(kuò)張細(xì)胞外基質(zhì)的異常代謝相關(guān)?3)何種來源的蛋白酶參與了冠脈擴(kuò)張的病程?4)哪些內(nèi)源性物質(zhì)能夠調(diào)控這些酶的作用?本研究期待明確蛋白酶與冠脈擴(kuò)張的關(guān)系,為進(jìn)一步的研究提供理論基礎(chǔ)。[研究方法]因?yàn)楣跔顒?dòng)脈管壁的主要細(xì)胞外基質(zhì)成分是彈力纖維、Ⅰ和Ⅲ型膠原纖維,本研究首先在血清中檢測(cè)這些細(xì)胞外基質(zhì)合成和降解的生物標(biāo)志物,以初步評(píng)估冠脈擴(kuò)張患者細(xì)胞外基質(zhì)代謝的總體情況,同時(shí)也研究了其中某些指標(biāo)的臨床診斷價(jià)值。進(jìn)而檢測(cè)血液中總彈性蛋白酶和總金屬基質(zhì)蛋白酶的活性變化,分析他們與冠脈擴(kuò)張細(xì)胞外基質(zhì)代謝的相關(guān)性,在這個(gè)結(jié)果的指導(dǎo)下：1)進(jìn)一步對(duì)中性粒細(xì)胞來源的蛋白酶及其內(nèi)源性抑制物做了系統(tǒng)的研究；2)系統(tǒng)篩查了冠脈擴(kuò)張患者外周血單個(gè)核細(xì)胞(peripheral blood mononuclear cells, PBMC)相關(guān)蛋白酶及其調(diào)控分子轉(zhuǎn)錄表達(dá)譜；3)利用冠脈擴(kuò)張混合血清模擬體內(nèi)的病理刺激,培養(yǎng)人臍靜脈平滑肌細(xì)胞,觀察其對(duì)蛋白酶表達(dá)和細(xì)胞外基質(zhì)代謝的影響,該部分還探討了細(xì)胞因子生長(zhǎng)分化因子15 (growth differentiation factor 15, GDF-15)的保護(hù)作用。[研究結(jié)果]通過對(duì)膠原代謝指標(biāo)系統(tǒng)檢測(cè)發(fā)現(xiàn)：冠脈擴(kuò)張患者彈性纖維降解增多,總膠原量減少,膠原極性由Ⅲ型為主向Ⅰ型為主轉(zhuǎn)化。這些變化可能與冠狀動(dòng)脈擴(kuò)張的形成,以及血管的硬化有密切的聯(lián)系。進(jìn)一步研究發(fā)現(xiàn),總彈性蛋白酶和總金屬質(zhì)蛋白酶(matrix metalloproteinase, MMP)與彈力纖維降解密切相關(guān)。其中彈性纖維的降解產(chǎn)物——可溶性彈力蛋白(soluble elastin, sElastin)有助于冠脈擴(kuò)張的輔助診斷。在這個(gè)基礎(chǔ)上開展的實(shí)驗(yàn)顯示：1)冠脈擴(kuò)張組的中性粒細(xì)胞以一種未知的方式激活,釋放出中性粒細(xì)胞彈性蛋白酶(human neutrophil elastase, HNE)和組織蛋白酶G (cathepsin G, CG),同時(shí)內(nèi)源性蛋白酶抑制物相應(yīng)升高來限制它們的過度破壞作用,但這些蛋白酶抑制物同時(shí)也抑制了纖溶酶,影響了纖溶系統(tǒng)的功能,理論上增加了冠脈擴(kuò)張血栓事件的概率。2)系統(tǒng)篩查單個(gè)核細(xì)胞的蛋白酶及其調(diào)控體系的表達(dá)譜發(fā)現(xiàn),單個(gè)核細(xì)胞來源的金屬基質(zhì)蛋白酶MMP1和MMP9,以及單個(gè)核細(xì)胞來源的細(xì)胞因子白細(xì)胞介素1α (interleukin-1A, IL1A)、血小板衍化生長(zhǎng)因子B(Platelet-derived growth factor B, PDGF-B)、干擾素γ(Interferon gamma, IFNγ)和GDF15,可能都參與到冠脈擴(kuò)張的疾病進(jìn)程。3)冠脈擴(kuò)張混合血清能上調(diào)人臍靜脈平滑肌細(xì)胞MMP1的表達(dá),加入GDF-15后這種上調(diào)高能夠被抑制,提示GDF-15是可能是一種內(nèi)源保護(hù)性因子。[研究結(jié)論]本研究以細(xì)胞外基質(zhì)代謝和蛋白酶解作用為中心開展了一系列的實(shí)驗(yàn),進(jìn)一步證實(shí)冠脈擴(kuò)張的主要機(jī)制是彈力纖維的破壞和膠原總量的減少,其中可溶性彈力蛋白sElastin有望新的輔助診斷指標(biāo)；參與冠脈擴(kuò)張的蛋白酶主要有：平滑肌細(xì)胞來源的MMP1,單個(gè)核細(xì)胞來源的MMP1和9,中性粒細(xì)胞來源的HNE和CG,同時(shí)機(jī)體還有一系列內(nèi)源性的物質(zhì)來調(diào)控蛋白酶的作用,包括數(shù)個(gè)蛋白酶抑制物和數(shù)個(gè)細(xì)胞因子,其中GDF15有潛力成為治療冠脈擴(kuò)張的一種藥物。本研究初步證實(shí)了蛋白酶與冠脈擴(kuò)張的密切關(guān)系,為后續(xù)的深入研究提供了理論基礎(chǔ)。
[Abstract]:[background] with the popularization of coronary imaging technology, coronary artery ectasia (CAE) is becoming more and more recognized by people. The incidence of coronary artery disease is low but the absolute number is large, and there are similar clinical manifestations of coronary heart disease. It is easy to have thrombus events and seriously harm the health and life of the patients. However, there is no pertinence to it at present. This is mainly due to the lack of clear etiology and pathogenesis. An in-depth study of the pathogenesis of coronary dilatation helps to scientifically formulate therapeutic strategies to alleviate the clinical symptoms and to improve the long-term prognosis. [Objective] the characteristic pathological manifestations of coronary dilatation are the components of the extracellular matrix of the middle layer of coronary artery. Serious damage, we propose that as the ultimate performer for the degradation of the extracellular matrix of the body, protease may play an important role in the abnormal metabolic process of the extracellular matrix of coronary dilatation. This study is intended to answer: 1) what are the characteristics of the extracellular matrix metabolism in coronary dilatation? 2) whether the protease is extended to the extracellular matrix of the coronary artery Abnormal metabolism related? 3) what is the source of protease involved in the course of coronary dilatation? 4) what endogenous substances can regulate the role of these enzymes? This study expects to clarify the relationship between protease and coronary dilatation and provide a theoretical basis for further research. [research methods] the main extracellular matrix component of the coronary artery wall is a projectile Force fibers, type I and type III collagen fibers. This study first examined the biomarkers of these extracellular matrix synthesis and degradation in serum to evaluate the overall status of the extracellular matrix metabolism in patients with coronary dilatation, and also to study the clinical diagnostic value of some of these indicators. Then, the total elastase and total gold in the blood were detected. The changes in the activity of matrix protease, analysis of their correlation with the metabolism of extracellular matrix of coronary dilatation, under the guidance of this result: 1) further study of neutrophil derived protease and its endogenous inhibitors; 2) systematic screening of peripheral blood mononuclear cells (peripheral blood Mo) in patients with coronary dilatation Nonuclear cells, PBMC) related proteases and their regulatory molecular transcriptional expression profiles; 3) the effects of cultured human umbilical vein smooth muscle cells on the expression of protease and the metabolism of extracellular matrix were observed by using coronary dilatation mixed serum to simulate the pathological stimulation in vivo, and the cytokine growth differentiation factor 15 (growth different) was also discussed. The protective effect of iation factor 15, GDF-15). [results] through the examination of the collagen metabolism index system, it was found that the degradation of elastic fibers in the patients with coronary artery dilatation was increased, the total amount of collagen was reduced, and the collagen polarity was mainly converted from type I to type I. These changes may be associated with the formation of coronary artery dilation and the hardening of blood vessels. Further studies have found that the total elastase and the total metal proteinase (matrix metalloproteinase, MMP) are closely related to the degradation of elastic fibers. The degradation products of the elastic fibers, soluble elastin (soluble elastin, sElastin), are helpful for the auxiliary diagnosis of coronary dilatation. 1) the neutrophils in the coronary dilatation group are activated in an unknown manner, releasing human neutrophil elastase (HNE) and cathepsin G (cathepsin G, CG), while endogenous protease inhibitors increase accordingly to limit their overdestruction, but these inhibitors also inhibit the activity of these protease inhibitors. Plasminase, which affects the function of fibrinolytic system, theoretically increases the probability of coronary dilatation thrombosis (.2), the expression profiles of the protease and its regulatory system of mononuclear cells, the metal matrix protease MMP1 and MMP9 from mononuclear cells, and the cytokine interleukin 1 alpha (Interl) from the single nuclear cell source. Eukin-1A, IL1A), platelet derived growth factor B (Platelet-derived growth factor B, PDGF-B), interferon gamma (Interferon gamma, IFN gamma) and GDF15, may be involved in the progression of coronary dilatation. It is suggested that GDF-15 is probably an endogenous protective factor. [Conclusion] this study conducted a series of experiments centered on extracellular matrix metabolism and proteolysis, and further confirmed that the main mechanism of coronary dilatation is the destruction of elastic fibers and the decrease of total collagen, in which the soluble elastin sElastin is expected to be new. The protease involved in coronary dilatation mainly include MMP1 of smooth muscle cells, MMP1 and 9 of mononuclear cells, HNE and CG derived from neutrophils, and a series of endogenous substances that regulate the role of protease, including several protease inhibitors and several cytokines, of which GDF15 has potential. Force has become a drug for the treatment of coronary dilatation. This study has preliminarily confirmed the close relationship between protease and coronary dilatation, which provides a theoretical basis for further further research.
【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】：2015
【分類號(hào)】：R541.4

【共引文獻(xiàn)】

相關(guān)期刊論文 前10條

1 王曰偉;李君;趙宗剛;戚森;劉軍軍;王豪夫;;人腹主動(dòng)脈瘤組織MMP-2和MMP-9表達(dá)及意義[J];青島大學(xué)醫(yī)學(xué)院學(xué)報(bào);2013年04期

2 戚潛輝;陳美苑;鐘成;范杰平;陳盛強(qiáng);;紅藤方對(duì)內(nèi)異癥MMP-9表達(dá)的影響[J];解剖學(xué)研究;2013年04期

3 尚松安;馬占龍;;血管平滑肌細(xì)胞與血管性病變發(fā)生的分子成像研究進(jìn)展[J];國際醫(yī)學(xué)放射學(xué)雜志;2013年05期

4 鄭海英;;冠狀動(dòng)脈慢血流現(xiàn)象相關(guān)因素分析[J];中國醫(yī)藥科學(xué);2013年23期

5 魏敦宏;付清海;�？鞓�;;血脂與冠狀動(dòng)脈慢血流的相關(guān)性分析[J];甘肅醫(yī)藥;2014年05期

6 靳飛鵬;蔣四華;馬雙陶;楊大春;楊永健;;高棕櫚酸飲食對(duì)ApoE基因敲除小鼠動(dòng)脈粥樣硬化的影響[J];國際心血管病雜志;2014年02期

7 何佳;黃薇薇;孟慶森;姜艷平;崔文;喬薪瑗;葛俊偉;劉敏;李一經(jīng);唐麗杰;;表達(dá)豬乳鐵蛋白的重組乳酸乳球菌對(duì)斷奶仔豬應(yīng)用效果的研究[J];動(dòng)物營(yíng)養(yǎng)學(xué)報(bào);2014年06期

8 張麗偉;蓋魯粵;;血管內(nèi)光學(xué)相干成像技術(shù)檢測(cè)易損斑塊研究進(jìn)展[J];第二軍醫(yī)大學(xué)學(xué)報(bào);2014年06期

9 趙文雅;王小兵;田海梅;李艷芬;李茉;張超;沈迪;齊軍;張偉;;巨噬細(xì)胞抑制因子-1聯(lián)合多種標(biāo)志物在結(jié)直腸癌診斷中的價(jià)值研究[J];癌癥進(jìn)展;2014年03期

10 付清海;魏敦宏;�？鞓�;史鋒慶;;冠狀動(dòng)脈慢血流與體質(zhì)指數(shù)相關(guān)性的臨床研究[J];甘肅醫(yī)藥;2014年07期

相關(guān)會(huì)議論文 前4條

1 羅鋼;趙立志;;冠脈造影診斷左房回旋支畸形遠(yuǎn)端動(dòng)脈瘤并左心房瘺1例[A];第十三次全國中西醫(yī)結(jié)合虛證與老年醫(yī)學(xué)學(xué)術(shù)研討會(huì)論文集[C];2013年

2 趙菁;俞曉軍;胡大一;丁榮晶;郭繼鴻;李學(xué)斌;張萍;王龍;王偉民;劉健;何飛;袁國裕;陳士良;高傳玉;趙洛沙;楚英杰;黃振文;邱春光;魏經(jīng)漢;滑少華;劉瑞云;;血栓抽吸導(dǎo)管聯(lián)合替羅非班在急性心肌梗死恢復(fù)期介入治療中的療效研究[A];《中華急診醫(yī)學(xué)雜志》第十二屆組稿會(huì)暨第五屆急診醫(yī)學(xué)青年論壇論文匯編[C];2013年

3 湯雄;袁濤;陶冶;;恩替卡韋、阿德福韋酯初始治療HbeAg陽性的慢性乙型肝炎的肝纖維化血清標(biāo)記及病理評(píng)價(jià)[A];江西省第三次中西醫(yī)結(jié)合肝病學(xué)術(shù)會(huì)議暨江西省中西醫(yī)結(jié)合肝病新進(jìn)展學(xué)習(xí)班論文匯編[C];2012年

4 陳靜廷;卜登攀;馬露;楊晉輝;張娟霞;李發(fā)第;;不同乳源牛乳中免疫球蛋白和乳鐵蛋白的比較研究[A];第四屆中國奶業(yè)大會(huì)論文集[C];2013年

相關(guān)博士學(xué)位論文 前10條

1 張璋;血管造影—FPA血液動(dòng)力學(xué)評(píng)估豬心外膜冠狀動(dòng)脈和微血管病變[D];天津醫(yī)科大學(xué);2012年

2 林曉紅;經(jīng)典瞬時(shí)受體電位通道在自發(fā)性高血壓大鼠頸動(dòng)脈重構(gòu)中的作用[D];福建醫(yī)科大學(xué);2013年

3 文鶴齡;雷公藤甲素對(duì)糖尿病大鼠心肌炎癥損傷的干預(yù)作用及機(jī)制[D];中南大學(xué);2013年

4 張旭婷;基底動(dòng)脈延長(zhǎng)擴(kuò)張癥的臨床表現(xiàn)及其與腦白質(zhì)病變的關(guān)系[D];浙江大學(xué);2013年

5 童光;HO-1介導(dǎo)心肌細(xì)胞κ-阿片受體激活的心肌保護(hù)作用及其機(jī)制研究[D];第四軍醫(yī)大學(xué);2013年

6 馬nI;不同CD4+T細(xì)胞亞群對(duì)動(dòng)脈粥樣硬化斑塊易損性和斑塊破裂的影響及其機(jī)制研究[D];山東大學(xué);2011年

7 張海峰;新型人源化抗CD20抗體的設(shè)計(jì)及生物學(xué)功能研究[D];第二軍醫(yī)大學(xué);2013年

8 陳越;營(yíng)養(yǎng)對(duì)嬰幼兒腦發(fā)育、認(rèn)知功能及代謝調(diào)控的影響[D];廈門大學(xué);2014年

9 許娜;基于炎性疾病組織重建的食品營(yíng)養(yǎng)學(xué)與疾病病理學(xué)機(jī)制研究[D];合肥工業(yè)大學(xué);2014年

10 郭楊志;益氣化痰活血法對(duì)AS粘附分子的影響及其與血脂異常證候的相關(guān)性[D];北京中醫(yī)藥大學(xué);2014年

相關(guān)碩士學(xué)位論文 前10條

1 薛玉剛;主動(dòng)脈瓣疾病對(duì)冠狀動(dòng)脈血流動(dòng)力學(xué)的影響[D];天津醫(yī)科大學(xué);2009年

2 韓冰;腦梗死復(fù)發(fā)與血清脂聯(lián)素的相關(guān)性研究[D];中國醫(yī)科大學(xué);2010年

3 姚義安;冠狀動(dòng)脈擴(kuò)張的發(fā)病機(jī)理初步探討與研究[D];中國協(xié)和醫(yī)科大學(xué);2009年

4 彭碧霞;冠狀動(dòng)脈彌漫性擴(kuò)張的影像特征與血流改變的關(guān)系[D];中南大學(xué);2010年

5 凌海平;中性粒細(xì)胞彈性蛋白酶在小鼠創(chuàng)傷性腦損傷后炎癥反應(yīng)中作用機(jī)制的研究[D];南方醫(yī)科大學(xué);2012年

6 托尼（Hasahya Tony）;[D];華中科技大學(xué);2012年

7 姚曉蒙;Exo70在大鼠血管平滑肌細(xì)胞中的定位與功能的初步研究[D];山東師范大學(xué);2013年

8 趙茹;實(shí)時(shí)心肌聲學(xué)造影定量評(píng)價(jià)缺血后適應(yīng)對(duì)微循環(huán)的影響[D];蘇州大學(xué);2013年

9 蘇琳涵;裕固族、漢族人群乳鐵蛋白基因多態(tài)性與齲病易感性的研究[D];蘭州大學(xué);2013年

10 李涵;MMP1及MMP3在心肌肥厚大鼠中的表達(dá)及奧美沙坦對(duì)其影響[D];鄭州大學(xué);2013年

，

本文編號(hào)：1905446