發(fā)布時間：2018-07-31 11:06

【摘要】：尋求新的保護(hù)因子或新的治療策略對心肌細(xì)胞(cardiac muscle cell,CM)的保護(hù)作用及其機(jī)制對于心臟疾病的治療和改善心功能具有重要的意義。雖然對心肌細(xì)胞肥大和心室重構(gòu)的研究取得了許多重大的突破性進(jìn)展,但這眾多的研究成果大多是基于心肌細(xì)胞或心室結(jié)構(gòu)本身而開展的,而對心臟神經(jīng)調(diào)控機(jī)制對心肌細(xì)胞結(jié)構(gòu)和功能的影響尚有待于從更廣和更深的層次開展研究。神經(jīng)調(diào)節(jié)蛋白-1β(neuregulin-1β,NRG-1β)可通過激活其酪氨酸激酶受體ErbB2和ErbB4而對神經(jīng)元發(fā)揮多種調(diào)控作用,NRG-1β很可能具備對心臟神經(jīng)發(fā)揮特有的調(diào)控作用的潛能,到目前為止,還沒有發(fā)現(xiàn)NRG-1β通過調(diào)控心臟神經(jīng)而對心肌發(fā)揮調(diào)控作用的報道。有趣的是,NRG-1β還可對心肌細(xì)胞直接發(fā)揮重要的調(diào)控功能。鑒于心臟神經(jīng)和心肌細(xì)胞均為NRG-1β直接調(diào)控的靶組織,這將使NRG-1β對心功能的調(diào)節(jié)作用機(jī)制更為復(fù)雜。本課題將基于以上研究背景開展如下一系列實驗研究:首先,研究NRG-1β對培養(yǎng)的新生大鼠心肌細(xì)胞的ErbB2和ErbB4受體及其下游的磷酸肌醇-3-激酶(phosphoinositide-3 kinase,PI3K)/蛋白激酶B(protein kinase B,PKB,Akt)和細(xì)胞外信號調(diào)節(jié)激酶 1/2(extracellular signal-regulated kinase 1/2,ERK1/2)的表達(dá)及其激活的影響作用;其次,研究NRG-1β及其相關(guān)的信號通路對心肌細(xì)胞重要的形態(tài)指標(biāo)和功能指標(biāo)的影響作用;最終,利用具有選擇性交感神經(jīng)支配的心肌細(xì)胞,研究NRG-1β及其相關(guān)的信號通路對神經(jīng)和心肌的雙重調(diào)控作用。通過以上系列研究,以便進(jìn)一步闡明NRG-1β直接調(diào)節(jié)心肌細(xì)胞或通過調(diào)節(jié)其神經(jīng)支配而調(diào)節(jié)心肌細(xì)胞的作用及其機(jī)制。從而提出不僅通過NRG-1β及其受體信號的活性而直接增強(qiáng)心肌細(xì)胞再生能力或功能,而且還可通過NRG-1β及其受體信號系統(tǒng)介導(dǎo)的心臟神經(jīng)調(diào)控作用而進(jìn)一步增強(qiáng)其對心肌細(xì)胞結(jié)構(gòu)和功能的調(diào)控作用的新的治療策略。第一部分神經(jīng)調(diào)節(jié)蛋白-1β在心肌細(xì)胞激活其受體及其下游信號通路的實驗研究NRG-1β對心肌細(xì)胞ErbB2和ErbB4受體及其下游的PI3K/Akt和ERK1/2的激活是其發(fā)揮生物學(xué)效應(yīng)的重要途徑。為了研究NRG-1β對心肌細(xì)胞ErbB2和ErbB4受體及其下游的信號分子Akt和ERK1/2表達(dá)及其激活的影響作用,本課題利用培養(yǎng)的新生大鼠心肌細(xì)胞觀察了 NRG-1β快速孵育和持續(xù)孵育對這些分子表達(dá)和激活的影響作用程度。結(jié)果顯示,NRG-1β急性孵育不會對心肌細(xì)胞表面積產(chǎn)生影響,而NRG-1β持續(xù)孵育,則可增加心肌細(xì)胞的表面積,有利于心肌細(xì)胞的生長發(fā)育;NRG-1β急性孵育雖然不能促進(jìn)其受體ErbB2和ErbB4及其下游信號分子Akt和ERK1/2的表達(dá),但可顯著提高其磷酸化水平,表明NRG-1β急性孵育可激活其受體及其相關(guān)的下游細(xì)胞信號轉(zhuǎn)導(dǎo)通路;NRG-1β持續(xù)孵育不僅能促進(jìn)其受體ErbB2和ErbB4及其下游信號分子Akt和ERK1/2的表達(dá),而且還使其磷酸化水平顯著上升,從而改善心肌細(xì)胞的生長狀態(tài);NRG-1β的促心肌細(xì)胞生長效應(yīng)可被PI3K抑制劑LY294002或ERK1/2抑制劑PD98059所阻斷,而不能阻斷NRG-1β的誘導(dǎo)其受體ErbB2和ErbB4表達(dá)和磷酸化的效應(yīng)。以上結(jié)果表明,NRG-1β急性孵育和NRG-1β持續(xù)孵育對心肌細(xì)胞具有不同的生物學(xué)效應(yīng)。NRG-1β急性孵育和NRG-1β持續(xù)孵育對其受體ErbB2和ErbB4及其下游信號分子Akt和ERK1/2表達(dá)和激活的不同生物學(xué)效應(yīng)揭示了將來利用NRG-1β治療相應(yīng)的心臟疾患所可能采取的不同治療策略。第二部分神經(jīng)調(diào)節(jié)蛋白-1β改善心肌細(xì)胞結(jié)構(gòu)和功能指標(biāo)的作用參與粗肌絲構(gòu)成的肌球蛋白重鏈(myosin heavy chain,MHC)、能夠激活調(diào)節(jié)性肌球蛋白輕鏈(myosin regulatory light chain,rMLC)的心肌特異的肌球蛋白輕鏈激酶(cardiac-specific myosin light-chain kinase,cMLCK)是調(diào)節(jié)肌節(jié)組裝的重要因子,心肌細(xì)胞的主要門控通道L-型鈣通道(L-type calcium channel,LTCC,Cav1.2)是Ca2+進(jìn)入心肌細(xì)胞的主要通道,肌質(zhì)網(wǎng)鈣離子三磷酸腺苷酶或肌質(zhì)網(wǎng)鈣離子泵(sarco(endo)plasmic reticulum Ca2+ ATPases or sarco(endo)plasmic reticulum-Ca2+ pump,SERCA2a)通過將胞質(zhì)內(nèi) Ca2+的轉(zhuǎn)運至肌質(zhì)網(wǎng)(sarcoplasmic reticulum,SR)內(nèi),從而調(diào)節(jié)收縮和舒張循環(huán)的協(xié)調(diào)性。以上指標(biāo)是影響心肌細(xì)胞結(jié)構(gòu)和功能的關(guān)鍵因素,為了檢測NRG-1β對這些指標(biāo)的影響作用及其相關(guān)機(jī)制,本課題利用培養(yǎng)的新生大鼠心肌細(xì)胞,研究了 NRG-1β及其相關(guān)的信號通路對心肌細(xì)胞的這些重要形態(tài)指標(biāo)和功能指標(biāo)的影響作用,并深入分析了 NRG-1β改善心肌細(xì)胞內(nèi)在組分的潛能。結(jié)果顯示,NRG-1β可分別促進(jìn)培養(yǎng)的心肌細(xì)胞代表性結(jié)構(gòu)指標(biāo)MHC、對心肌細(xì)胞內(nèi)的關(guān)鍵激酶cMLCK、代表性功能指標(biāo)L-型鈣通道和SERCA2a的表達(dá),P13K抑制劑LY294002或ERK1/2抑制劑PD98059可抑制NRG-1β引起的促心肌細(xì)胞MHC、cMLCK、L-型鈣通道和SERCA2a表達(dá)上調(diào)的作用。這些結(jié)果表明,NRG-1β可有效促進(jìn)對心肌細(xì)胞收縮的基本結(jié)構(gòu)分子和功能分子的表達(dá),從而改善心肌細(xì)胞的內(nèi)在組分構(gòu)成,并由此而提高心肌細(xì)胞功能的潛在能力,這是NRG-1β將來有可能成為改善心功能的有效治療分子的重要實驗依據(jù)。第三部分神經(jīng)調(diào)節(jié)蛋白-1β增強(qiáng)心肌細(xì)胞去甲腺素能命運的潛能心肌細(xì)胞的去甲腎上腺素能命運是保證和維持心肌細(xì)胞功能的前提,在此基礎(chǔ)上,心肌細(xì)胞的功能調(diào)控還有賴于正常交感神經(jīng)的支配。心肌細(xì)胞β-腎上腺素能受體(β-adrenergic receptor,β-AR)的表達(dá)是心肌細(xì)胞的去甲腎上腺素能命運的重要體現(xiàn),β-AR的激活是交感神經(jīng)支配信號傳遞的必由途經(jīng)。本課題將根據(jù)NRG-1β及其相關(guān)的信號通路對神經(jīng)和心肌的雙重調(diào)控作用,建立器官型的頸上神經(jīng)節(jié)(superior cervical ganglion,SCG)組織塊和分散心肌細(xì)胞的聯(lián)合培養(yǎng)體系,研究有或沒有交感神經(jīng)支配的培養(yǎng)的心肌細(xì)胞,再附加NRG-1β孵育的條件下,心肌細(xì)胞去甲腎上腺素能命運潛能的變化。結(jié)果顯示,NRG-1β孵育可使心肌細(xì)胞β1-AR和β2-AR的表達(dá)水平上調(diào),而選擇性交感神經(jīng)支配使心肌細(xì)胞β1-AR和β2-AR表達(dá)水平上調(diào)的效應(yīng)更加明顯,NRG-1β孵育可進(jìn)一步增強(qiáng)交感神經(jīng)支配信號對心肌細(xì)胞β1-AR和β2-AR表達(dá)水平上調(diào)的促進(jìn)效應(yīng);在心肌細(xì)胞與交感神經(jīng)元聯(lián)合培養(yǎng)的過程中,應(yīng)用NRG-1β孵育能夠通過增加交感神經(jīng)元突起的數(shù)目增強(qiáng)交感神經(jīng)信號對心肌細(xì)胞支配的效能;PI3K抑制劑LY294002或ERK1/2抑制劑PD98059可抑制NRG-1β引起的促心肌細(xì)胞β1-AR和β2-AR表達(dá)上調(diào)作用和促神經(jīng)元突起生長的效應(yīng)。這些結(jié)果表明,NRG-1β具有進(jìn)一步增強(qiáng)交感神經(jīng)支配信號的促心肌細(xì)胞去甲腎上腺素能命運的效應(yīng),這一效應(yīng)是通過PI3K/Akt和ERK1/2細(xì)胞信號轉(zhuǎn)導(dǎo)通路介導(dǎo)的。本課題的研究結(jié)果對于以NRG-1β及其受體信號系統(tǒng)為主導(dǎo)的具有針對性的治療策略的制定提供了具有指導(dǎo)意義的理論基礎(chǔ)和具有參考價值的實驗依據(jù)。
[Abstract]:The protective effect of new protective factors or new therapeutic strategies on cardiac muscle cell (CM) and its mechanism are of great significance for the treatment of heart disease and the improvement of cardiac function. Although many major breakthroughs have been made in the study of cardiac myocyte hypertrophy and ventricular remodeling, many research achievements have been made. Many of them are based on cardiac myocytes or ventricular structure itself, and the effect of the cardiac nerve regulation mechanism on the structure and function of cardiac myocytes remains to be studied from a broader and deeper level. The neuroregulatory protein -1 beta (neuregulin-1 beta, NRG-1 beta) can play a role in neurons by activating its tyrosine kinase receptor ErbB2 and ErbB4. A variety of regulatory functions, NRG-1 beta is likely to have the potential to play a unique regulatory role in the heart nerve. Up to now, there has been no discovery of the regulation of the NRG-1 beta by regulating the heart nerve. It is interesting that NRG-1 beta can also play an important regulatory function on cardiac myocytes. All the cells are the target tissues directly regulated by NRG-1 beta, which will make the regulatory mechanism of NRG-1 beta more complex. This topic will be based on a series of experimental studies based on the above research background. First, the ErbB2 and ErbB4 receptors of NRG-1 beta cultured neonatal rat cardiomyocytes and their downstream inositol -3- kinase (phosphoi) are studied. Nositide-3 kinase, PI3K) / protein kinase B (protein kinase B, PKB, Akt) and the expression of extracellular signal regulated kinase 1/2 (extracellular signal-regulated) and its effect on activation; secondly, the effect of beta and its related signal pathways on the important morphological and functional indexes of cardiac myocytes; Finally, using the cardiomyocytes with selective sympathetic innervation, the dual regulatory role of NRG-1 beta and its related signaling pathway on the nerve and myocardium is studied. Through the above series of studies, the role and mechanism of NRG-1 beta regulating cardiac myocytes directly or regulating the innervation of the cardiac myocytes by regulating their innervation are further elucidated. A new therapeutic strategy is proposed to enhance the ability or function of cardiac myocyte regeneration not only through the activity of NRG-1 beta and its receptor signal, but also through the regulatory role of the cardiac nerve in the NRG-1 beta and its receptor signaling system. Experimental study of white -1 beta activation of its receptor and its downstream signaling pathway in cardiac myocytes: NRG-1 beta activation of ErbB2 and ErbB4 receptors and its downstream PI3K/Akt and ERK1/2 is an important pathway for its biological effects. In order to study the expression of NRG-1 beta on ErbB2 and ErbB4 receptors and the downstream signaling molecules Akt and ERK1/2 expression of NRG-1 beta The effect of NRG-1 beta incubation and continuous incubation on the expression and activation of these molecules was observed by the cultured neonatal rat cardiomyocytes. The results showed that the acute incubation of NRG-1 beta did not affect the surface area of cardiac myocytes, while NRG-1 beta incubation could increase the myocardial cells. The surface area is beneficial to the growth and development of cardiac myocytes; the acute incubation of NRG-1 beta can not promote the expression of its receptor ErbB2 and ErbB4 and their downstream signal molecules Akt and ERK1/2, but can significantly increase their phosphorylation level. It indicates that the acute incubation of NRG-1 beta can activate its receptor and its related downstream cell signal transduction pathway; NRG-1 beta incubates continuously. It can not only promote the expression of its receptor ErbB2 and ErbB4 and their downstream signal molecules Akt and ERK1/2, but also increase their phosphorylation level significantly, thus improving the growth state of cardiac myocytes; the growth effect of NRG-1 beta myocytes can be blocked by PI3K inhibitor LY294002 or ERK1/2 inhibitor PD98059, but can not block the induction of NRG-1 beta. The effects of receptor ErbB2 and ErbB4 expression and phosphorylation show that NRG-1 beta acute incubation and NRG-1 beta incubation have different biological effects on cardiac myocytes with different biological effects of.NRG-1 beta incubation and NRG-1 beta incubation on the different biological effects of ErbB2 and ErbB4 and its downstream signal molecules Akt and ERK1 /2 expression and activation. The different treatment strategies may be taken in the future using NRG-1 beta for the treatment of corresponding cardiac disorders. The role of the second part of the neuromodulation protein -1 beta to improve the structure and function of cardiac myocytes is involved in the myosin heavy chain (myosin heavy chain, MHC), which can stimulate the light chain (myosin regulatory lig) of the myosin (myosin regulatory lig). The myocardial specific myosin light chain kinase (cardiac-specific myosin light-chain kinase, cMLCK) of HT chain, rMLC is an important factor regulating the assembly of myosine, the main gated channel of cardiac myocytes is the L- type calcium channel (L-type calcium channel) is the main channel to enter the cardiac myocytes, and the calcium ion three phosphate gland of the sarcoplasmic reticulum Sarco (Endo) plasmic reticulum Ca2+ ATPases or sarco (Endo) plasmic reticulum-Ca2+ pump, which regulates the coordination of contractile and diastolic circulation by transferring the cytoplasm to the sarcoplasmic reticulum. The above index is the key to the structure and function of the cardiac myocytes. Key factors, in order to detect the effect of NRG-1 beta on these indexes and their related mechanisms, we used the cultured neonatal rat cardiomyocytes to study the effects of NRG-1 beta and related signal pathways on these important morphological and functional indexes of cardiac myocytes, and the improvement of NRG-1 beta to improve the internal group of cardiac myocytes. The results showed that NRG-1 beta could promote the representative structural index MHC of cultured cardiac myocytes, the key kinase cMLCK in the cardiac myocytes, the expression of L- type calcium channel and SERCA2a, the P13K inhibitor LY294002 or ERK1/2 inhibitor PD98059 could inhibit the MHC, cMLCK, and calcium channel induced by NRG-1 beta. These results suggest that NRG-1 beta can effectively promote the expression of the basic structural molecules and functional molecules of cardiac myocyte contraction, thus improving the intrinsic composition of cardiac myocytes and thereby enhancing the potential ability of cardiac myocyte function, which is an effective treatment for NRG-1 beta in the future to improve cardiac function. The third part of the neuromodulation protein -1 beta enhances the fate of noradrenalin in cardiac myocytes, the fate of noradrenalin in cardiac myocytes is the prerequisite to guarantee and maintain the function of cardiac myocytes. On this basis, the function regulation of cardiac myocytes depends on the control of normal sympathetic nerve. The expression of adrenergic receptor (beta -adrenergic receptor, beta -AR) is an important manifestation of the fate of noradrenalin in cardiac myocytes. The activation of beta -AR is a must by the transmission of sympathetic innervation signal. This subject will establish an organotypic neck based on the dual regulatory effect of NRG-1 beta and its related signal pathways on the nerve and myocardium. A joint culture system of the superior cervical ganglion (SCG) tissue and scattered myocardial cells to study the cultured cardiac myocytes with or without sympathetic innervation, and then add NRG-1 beta incubation to change the fate potential of norepinephrine in the cardiomyocytes. The results show that NRG-1 beta incubation can make myocardial cells beta 1-AR. And the expression level of beta 2-AR was up-regulated, and the effect of selective sympathetic innervation on the up regulation of beta 1-AR and beta 2-AR expression was more obvious. NRG-1 beta incubation could further enhance the promotion effect of sympathetic innervation signal on the up regulation of the expression level of beta and beta 2-AR in cardiac myocytes, and Co culture of cardiac myocytes and sympathetic neurons. In the process, NRG-1 beta incubation can enhance the efficacy of sympathetic nerve signal to cardiac myocytes by increasing the number of sympathetic neurites. The PI3K inhibitor LY294002 or ERK1/2 inhibitor PD98059 inhibits the effect of NRG-1 beta induced up-regulated expression of beta 1-AR and beta 2-AR and promoting the growth of neuronal protrusion. The results suggest that NRG-1 beta has the effect of further enhancement of sympathetic innervation signal to the fate of noradrenaline, which is mediated by the PI3K/Akt and ERK1/2 cell signal transduction pathways. The results of this study are targeted at the targeted treatment strategy based on the NRG-1 beta and its receptor signaling system. The formulation provides a theoretical basis and a theoretical basis for reference.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R54

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