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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 王淑美(Seu-Mei Wang) | |
dc.contributor.author | Hsiu-Chi Ding | en |
dc.contributor.author | 丁修齊 | zh_TW |
dc.date.accessioned | 2021-06-15T04:46:21Z | - |
dc.date.available | 2012-09-09 | |
dc.date.copyright | 2010-09-09 | |
dc.date.issued | 2010 | |
dc.date.submitted | 2010-08-05 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/45800 | - |
dc.description.abstract | 對甲酚 (p-cresol),是一種與蛋白質結合的尿毒素 (uremic toxin),緣自於酪胺酸 (tyrosine) 經腸道細菌發酵後的代謝產物。慢性腎臟病變 (chronic kidneydisease) 的病患,由於腎絲球過濾率 (glomerular filtration rate) 下降,導致血液中對甲酚的含量增加。近期的研究報告指出對甲酚與心血管疾病具有顯著的相關性。然而至目前為止,對甲酚是否會損傷心肌細胞及其機制仍待研究。所以本研究擬探討對甲酚對於新生大白鼠心肌細胞間隙接合 (gap junction) 的影響及其機轉。心肌細胞以對甲酚處理不影響細胞的存活度,也不會造成細胞的凋亡及壞死,且隨著處理時間增加,心肌細胞自發性收縮速率降低且具有可逆性。利用免疫螢光染色發現connexin43 (Cx43) 於心肌細胞接合處的點狀染色分布減少且變小,顯示Cx43 已去組合,且此現象亦具有可逆性。接著利用scrape loading /dyetransfer 技術評估間隙接合的功能,發現對甲酚處理後dye transfer 的距離會減少,證實對甲酚會降低心肌細胞間隙接合溝通 (GJIC) 的功能。流式細胞儀證明對甲酚會引起心肌細胞內活性氧化物及鈣離子濃度增加;我們也發現PKCα磷酸化(活化)上升,且加入抗氧化劑N-acetylcystein (NAC) 及鈣離子螯合劑BAPTA-AM 可抑制PKCα磷酸化的上升。使用西方墨點分析法證明對甲酚處理造成去磷酸化Cx43 (NP-Cx43 及triton X-100 soluble P0 Cx43) 表現量上升及P2+P1 Cx43 表現量下降,而Cx43 去磷酸化被認為會造成間隙接合去組合及GJIC 下降。加入PKCα/βI 抑制劑Gö6976 可以抑制對甲酚引起的P2+P1 Cx43 磷酸化下降、NP-Cx43 表現量的上升及NP-Cx43 於細胞質中的染色;加入抗氧化劑NAC 及鈣離子螯合劑BAPTA-AM 可抑制NP-Cx43 表現量的上升,上述抑制劑均可抑制對甲酚所造成之Cx43 去組合及GJIC 下降。以上實驗結果顯示對甲酚可能藉由增加細胞內活性氧化物及鈣離子濃度進而活化PKCα訊息傳遞路徑使Cx43 去磷酸化,並造成Cx43 去組合及GJIC 下降。另外,對甲酚處理後ROCK 下游受質MYPT-1 (myosin light chain phosphatase-1)磷酸化程度增加,顯示ROCK 的活化。ROCK (Rho-kinase) 抑制劑Y27632 可抑制對甲酚引起之PKCα磷酸化、NP-Cx43表現量上升、Cx43 去組合及間隙接合功能異常。所以此激酶位於PKCα的上游,也參與了對甲酚影響接隙接合的分佈及功能之訊息傳遞。我們也預先處理去磷酸化酶抑制劑calyculin A 及okadaic acid,發現calyculinA 及okadaic acid 可阻止因對甲酚引起間隙接合的變化,顯示絲胺酸/蘇胺酸去磷酸化酶可能也參與了對甲酚對於間隙接合的影響。 | zh_TW |
dc.description.abstract | p-cresol, a protein-bound uremic toxin, is a colonic bacterial fermentation metabolite of the amino acid tyrosine. In chronic kidney disease patients, decrease of glomerular filtration rate results in increased plasma levels of p-cresol. Recent studies indicate that p-cresol is significantly related to cardiovascular diseases. However, whether p-cresol directly affects cardiomyocytes and the mechanisms underlying p-cresol-induced damage remain to be investigated. Therefore, the purpose of this study was to investigate the effects of p-cresol on gap junctions in primary cultured neonatal cardiomyocytes. p-cresol did not affect cell viability, cell apoptosis and necrosis. p-cresol reduced the spontaneous contraction rates of cardiomyocytes in atime-dependent manner and this phenomenon was reversible. In immunofluorescence study, Cx43 dots of cardiomyocytes at cell-cell junctions are decreased by p-cresol treatment, suggesting Cx43 disassembly and this phenomenon was also reversible. In functional study of scrape loading dye transfer assay, the distance of dye transfer became shorten after p-cresol treatment, confirming that p-cresol impaired gap junction intercellular communication (GJIC). We demonstrated that reactive oxygen species (ROS) and [Ca2+] i increased after p-cresol treatment using flow cytometry. p-cresol also induced PKCα | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T04:46:21Z (GMT). No. of bitstreams: 1 ntu-99-R97446004-1.pdf: 4206357 bytes, checksum: 742a6e38e2dda15d057d521a0483fa9c (MD5) Previous issue date: 2010 | en |
dc.description.tableofcontents | 誌謝... i
中文摘要 ii Abstract iv 目 錄 1 第一章 緒論 4 一、對甲酚及其毒性之相關研究 4 二、對甲酚與心血管疾病之關係 5 三、蛋白質激酶 C 6 四、絲胺酸/蘇胺酸去磷酸酶 7 五、Rho-kinase及myosin light chain phosphatase 8 六、間隙接合 9 七、研究動機 11 第二章 材料與方法 13 一、新生大白鼠心肌細胞初級培養 (primary cell culture) 13 二、心肌收縮速率的測量 14 三、DAPI及PI 染色 14 四、MTT試驗 14 五、實驗使用之抗體及藥物 (antibodies and drugs) 14 六、藥物處理 (drug treatment) 17 七、免疫螢光染色 (immunofluorescence staining) 17 八、Scrape loading/dye transfer (SL/DT) 17 九、流式細胞儀分析 (flow cytometry analysis) 18 十、西方墨點分析法 (Western blot analysis) 18 十一、Triton X-100萃取蛋白質 (triton X-100 protein extraction) 20 十二、統計分析 (statistic analysis) 20 第三章 實驗結果 21 一、對甲酚對於心肌細胞存活度的影響 21 二、心肌細胞收縮速率隨著對甲酚處理的時間增加而下降且具有可逆性 21 三、對甲酚對於心肌細胞Cx43分佈的影響及其可逆性 22 四、對甲酚對於心肌細胞間隙接合蛋白功能的影響 23 五、對甲酚藉由增加活性氧化物、鈣離子及活化ROCK與PKCa影響Cx43之分佈及GJIC 24 六、對甲酚引發細胞內活性氧化物及鈣離子濃度增加並活化PKCa 25 七、對甲酚藉由活化PKCa造成total Cx43磷酸化程度下降及影響NP-Cx43之分佈 26 八、對甲酚可能活化絲胺酸/蘇胺酸蛋白質去磷酸酶影響Cx43分佈變化 27 九、對甲酚處理活化ROCK下游受質MYPT-1 27 第四章 討論 29 第五章 參考文獻 35 第六章、圖片及圖片說明 44 圖1、對甲酚對於心肌細胞存活度的影響 44 圖2、對甲酚處理使心肌細胞收縮速率下降 45 圖3、不同濃度對甲酚處理對於心肌細胞Cx43分佈的影響 46 圖4、短時間對甲酚處理對於心肌細胞Cx43分佈的影響 47 圖5、長時間對甲酚處理對於心肌細胞Cx43分佈的影響 48 圖6、對甲酚對於心肌細胞Cx43分佈的影響具有可逆性 49 圖7、對甲酚對於心肌細胞GJIC的影響 51 圖8、NAC、BAPTA-AM、Gö6976及Y27632對於對甲酚處理之心肌細胞Cx43分佈之影響 52 圖9、NAC、BAPTA-AM、Gö6976及Y27632對於對甲酚處理之心肌細胞GJIC之影響 54 圖10、對甲酚處理引發細胞內活性氧化物及鈣離子濃度上升 55 圖11、對甲酚處理活化PKCa及NAC、BAPTA-AM與Y27632對於PKCa活化的影響 57 圖12、對甲酚處理造成Cx43磷酸化程度下降 59 圖13、抑制劑Gö6976對於total Cx43的影響 60 圖14、對甲酚處理對NP-Cx43表現的影響及NAC、BAPTA-AM、Gö6976及Y27632對於NP-Cx43的影響 62 圖15、對甲酚處理造成Triton-soluble P0 Cx43表現量上升 64 圖16、Gö6976對於對甲酚處理之心肌細胞NP-Cx43分佈之影響 65 圖17、絲胺酸/蘇胺酸去磷酸酶抑制劑calyculin A及okadaic acid對於對甲酚處理之心肌細胞Cx43分佈之影響 66 圖18、對甲酚處理對MYPT-1表現的影響 67 附錄一、Cx43結構圖及磷酸化位置圖 68 附錄二、模式圖 69 附錄三、英文專業名稱縮寫 70 | |
dc.language.iso | zh-TW | |
dc.title | 對甲酚對於新生大鼠心肌細胞間隙接合的影響 | zh_TW |
dc.title | Effects of p-cresol on Gap Junction in Neonatal Rat
Cardiomyocytes | en |
dc.type | Thesis | |
dc.date.schoolyear | 98-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 吳建春(Jiahn-Chun Wu),陳玉怜(Yuh-Lien Chen),鄭瓊娟(Chung-Jiuan Jeng) | |
dc.subject.keyword | 間隙接合蛋白43,間隙接合,鈣離子,活性氧化物,心律不整,對甲酚,心肌細胞,蛋白質激酶,C,Rho激酶,肌凝蛋白輕鏈去磷酸酶,第一型蛋白質去磷酸酶,第二型蛋白質去磷酸酶,A,間隙接合細胞間溝通, | zh_TW |
dc.subject.keyword | Cx43,gap junction,Ca++,ROS,arrhythmia,p-cresol,cardiomyocyte,PKC,ROCK,MYPT-1,PP1,PP2A,GJIC, | en |
dc.relation.page | 71 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2010-08-05 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 解剖學暨生物細胞學研究所 | zh_TW |
顯示於系所單位: | 解剖學暨細胞生物學科所 |
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