本文選題：EGCG + 心臟舒張功能障礙��； 參考：《重慶醫(yī)科大學(xué)》2017年碩士論文

【摘要】：表沒食子兒茶素沒食子酸酯(EGCG)源于茶多酚,具有多種生物活性。EGCG可以降低組蛋白去乙�；�(HDACs)的活性,從而調(diào)控基因的表達(dá)。本課題組前期對(duì)cTnI R193H限制型心肌病模型小鼠研究發(fā)現(xiàn),正常cTnI表達(dá)降低、而突變cTnI異常表達(dá)是限制性心肌病(RCM)發(fā)病機(jī)制之一。研究還發(fā)現(xiàn),EGCG干預(yù)R193H模型小鼠,可以降低模型小鼠心肌細(xì)胞對(duì)鈣的敏感性,改善其舒張功能。本課題組前期對(duì)老年小鼠的研究發(fā)現(xiàn),老年小鼠存在衰老性舒張功能障礙并同時(shí)伴有cTnI表達(dá)降低,給予EGCG可明顯升高老年小鼠cTnI的表達(dá),改善其衰老性舒張功能障礙。為此提出科學(xué)假設(shè):EGCG還可能通過上調(diào)R193H小鼠正常cTnI的表達(dá),參與改善舒張功能障礙。目的本實(shí)驗(yàn)利用EGCG對(duì)cTnI R193H模型小鼠進(jìn)行3個(gè)月干預(yù),以期探尋EGCG升高模型小鼠心臟正常cTn I的表達(dá)量,及其組蛋白乙�；恼{(diào)控機(jī)理。方法選擇8周齡的健康spf級(jí)c57bl/6小鼠和ctnir193h雄性小鼠各30只,兩種小鼠均分別分成egcg干預(yù)組、dmso干預(yù)組以及未干預(yù)組。egcg干預(yù)采用腹腔注射溶于dmso的egcg,按照各個(gè)小鼠體重,每1kg體重給予egcg50mg,dmso干預(yù)采用腹腔注射與egcg干預(yù)組溶劑容積一致的dmso,未干預(yù)組僅進(jìn)行腹腔注射行為,但不注射。每周干預(yù)5天,干預(yù)3個(gè)月后收集各組小鼠心臟組織。分別用westernblot、rt-pcr、chip-q-pcr檢測(cè)ctni的表達(dá)量;ctni、gata4及hdac1的mrna表達(dá)水平;ctni基因啟動(dòng)子區(qū)hdac1、gata4的結(jié)合水平及組蛋白h3k9乙�；�。結(jié)果r193h小鼠心臟egcg干預(yù)組與dmso干預(yù)組和未干預(yù)組比較結(jié)果顯示:1.r193h小鼠egcg干預(yù)組正常ctni的表達(dá)量在mrna及蛋白水平均升高(p0.05),而正常的野生型c57小鼠則無此變化。2.r193h小鼠egcg干預(yù)組gata4的mrna表達(dá)水平升高,hdac1的mrna表達(dá)水平降低(p0.05)。3.r193h小鼠egcg干預(yù)組組蛋白h3k9乙�；缴�,ctni啟動(dòng)子區(qū)域hdac1結(jié)合水平降低,gata4的結(jié)合水平升高(p0.05)。結(jié)論egcg可通過抑制hdac1的表達(dá)及hdac1在ctni啟動(dòng)子區(qū)域的結(jié)合,促進(jìn)組蛋白h3k9的乙�；⑿呐K核心轉(zhuǎn)錄因子gata4的表達(dá)及gata4在ctni啟動(dòng)子區(qū)域的結(jié)合,上調(diào)限制型心肌病心肌正常ctni的表達(dá)。
[Abstract]:Epigallocatechin gallate (EGCG) is derived from tea polyphenols. EGCG can reduce the activity of histone deacetylase (HDACs) and regulate gene expression. The previous study of mice with cTnI R193H restricted cardiomyopathy showed that the expression of normal cTnI was decreased, and the abnormal expression of mutant cTnI was one of the pathogenesis of restrictive cardiomyopathy (RCM). It was also found that EGCG could decrease the sensitivity of cardiac myocytes to calcium and improve the diastolic function of R193H model mice. In the early stage of the study, we found that senile diastolic dysfunction and decreased cTnI expression were found in the aged mice. EGCG could significantly increase the expression of cTnI and improve the aging diastolic dysfunction in the aged mice. Therefore, the scientific hypothesis is that EGCG may be involved in improving diastolic dysfunction by up-regulating the expression of normal cTnI in R193H mice. Objective in this study, EGCG was used to intervene cTnI R193H model mice for 3 months, in order to explore the expression of normal cTnI and the regulation mechanism of histone acetylation. Methods A total of 30 healthy spf grade c57bl/6 mice and 30 ctnir193h male mice were randomly divided into two groups: the egcg intervention group and the non-intervention group. The mice were injected intraperitoneally with dmso soluble egcg according to the weight of each mouse. Each 1kg was treated with egcg 50mg / dmso by intraperitoneal injection with the same solvent volume as that in the egcg intervention group, but not by intraperitoneal injection in the non-intervention group. Heart tissues were collected after intervention for 5 days a week for 3 months. The expression level of ctni and mrna of hdac1 were detected by Western blottl rt-pcrtip-q-PCR, respectively. The binding level of hdac1 and gata4 in promoter region of CTNI gene and the acetylation level of histone h3k9 were detected. Results compared with dmso intervention group and dmso intervention group, the expression of normal ctni in egcg intervention group was higher than that in dmso intervention group (p0.05), while that in normal wild-type c57 mice was not. 2. R193h mice. The level of mrna expression of gata4 in egcg intervention group was increased (p0.05). The mrna expression of hdac1 was decreased (p0.05). 3. The level of h3k9 acetylation of histone was increased in egcg intervention group. The level of hdac1 binding in the promoter region of ctni decreased significantly (p0.05). Conclusion egcg can promote the acetylation of histone h3k9, the expression of heart core transcription factor gata4 and the binding of gata4 to ctni promoter by inhibiting the expression of hdac1 and the binding of hdac1 in ctni promoter region. To upregulate the expression of normal ctni in myocardium of restricted cardiomyopathy.
【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R725.4

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