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研究生： 何致緯
Ho, Chih-Wei
論文名稱： Palladin 於大鼠心肌細胞中的分化與發育
The Role of Palladin in Cardiomyocyte Differentiation and Development
指導教授： 王浩文
Wang, Hao-Ven
學位類別： 碩士
Master
系所名稱： 生物科學與科技學院 - 生命科學系
Department of Life Sciences
論文出版年： 2019
畢業學年度： 107
語文別： 中文
論文頁數： 103
中文關鍵詞： Palladin 、cardiomyocyte differentiation 、Nebulette 、H9c2.
外文關鍵詞： Palladin, cardiomyocyte differentiation, Nebulette, H9c2.
相關次數： 點閱：127  下載：0 
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    • Palladin為一種微絲結合蛋白(actin-binding protein, ABP)，ABP可以與肌動蛋白微絲(actin filament)互相結合，參與調控細胞活動，例如細胞遷移、分裂、維持細胞結構與分化，palladin屬於myotilin/myopalladin/palladin家族一員，其中palladin因為不同起始位置以及選擇性剪切而有不同的isoform，目前受到最廣泛研究的為200、140、90 kDa isoform，先前的研究已經知道palladin (140~90 kDa)會和nebulette splicing form Nebl(1014 AA)的C端的SH3 domain產生直接的交互作用，而palladin(200~140 kDa)以及palladin(90 kDa)則不會。但此一交互作用是否影響心肌細胞的分化尚不清楚。本篇研究主要探討palladin對於心肌細胞分化的影響以及palladin與Nebulette在心肌分化過程中的分布位置。我們首先製備fibroblast-derived matrix (FDM)以提供細胞更易於分化的微環境，之後施以含低濃度血清分化培養基DMEM促使細胞分化，並分別使用西方墨點法與免疫螢光染色觀察蛋白表現與分布位置。結果發現細胞於FDM環境中與低濃度血清培養基培養下可以從myoblast分化至mature cardiomyocyte。心肌細胞分化標記蛋白表現逐漸上升，palladin 90 kDa先升後降，140 kDa為下降趨勢，200 kDa則無明顯表達，Nebulette則有先降後升的趨勢。在蛋白分布方面可以發現這些蛋白都與actin有共區域化的現象。在觀察完正常情況下蛋白的表現與分佈後。我們進行palladin siRNA轉染將palladin knockdown以阻止palladin與nebulette在心肌中的交互作用，但從結果來看可以發現只抑制了palladin 90 kDa isoform的表現，從後續的西方墨點法分析可以發現，心肌母細胞依然可以正常分化，從免疫螢光染色圖可以發現細胞分化初期的速度有加快的趨勢。本篇結果得到抑制palladin 90 kDa isoform的表現也許不會干擾palladin與Nebulette在心肌中的交互作用，但卻影響心肌母細胞分化初期的速度，在未來還需透過更多研究釐清palladin各種isoform參與心肌分化的機制。

    Palladin is an actin associated protein reported to play an important role in regulating cell adhesion and cytoskeletal organization. As a member of the paladin/myotilin/myopalladin family, palladin has been categorized into 90 kDa, 140 kDa, and 200 kDa isoforms. Each of them is a widely expressed and can be at stress fibers, focal adhesions, Z-discs, as well as various actin-based subcellular structures. Nebulette, a homologous thin filament-associated proteins of nebulin, is a cardiac-specific isoform belonging to the nebulin proteins family in cardiac muscles. Nebulette, a cardiac-specific isoform is involved in various important protein-protein interactions. Several data showed the contribution of nebulette in the integrity of myocardial function and palladin has been shown to interact directly with nebulette. Based on these findings, we hypothesized that palladin-nebulette interaction may affect cardiac muscle cells differentiation. However, the role of palladin in cardiomyocyte differentiation is remanded unknown. The aim of this study is to determine the contribution of palladin to cardiomyocyte differentiation. Firstly, we generated a fibroblast-derived matrix (FDM) as a novel extra cellular matrix (ECM) platform to enhance rat cardiomyocyte H9c2 differentiation. Total protein was extracted from H9c2 cells then it was performed with antibodies against α-actinin 2, cardiac troponin T, nebulette and the three palladin isoforms to know level of protein expression at various differentiation stages. Immunofluorescence method was also used to localize cardiac differentiation markers within the cells. Finally, we knockdown palladin 90 kDa in cultured H9c2 cell by using siRNA transfection technic and studied the difference in protein expression by western blot and immunofluorescence. Compared to our control group cells, palladin-knockdown group did not show significant defect on cell differentiation. Nevertheless, in palladin knockdown cells nebulette tend to quickly spread in the cell while poly palladin spreading rate is reduced yet it colocalize with F-actin. Taken together, our finding suggest that palladin plays a potential important role in cardiomyocyte differentiation. We hope our research will provide more insight in the role of palladin in cardiomyocyte early stage differentiation and thus in cardiomyopathy studies.

    摘要 I 英文延伸摘要 II 致謝 VII 目錄 VIII 圖目錄 XI 1. 前言 1 1.1 微環境對心肌分化的影響 1.2 細胞骨架對於心肌分化的重要性 1.3 Actin-binding protein, palladin 1.4 Palladin對於細胞分化的重要性 1.5 Nebulette 1.6 Palladin與Nebulette的交互作用 1.7 研究目的 2. 實驗材料與方法 8 2.1 細胞株來源 2.2 細胞增殖(growth)、分化(differentiation)培養基配製 2.3 細胞解凍與培養 2.4 細胞繼代與計數 2.5 FDM製備 2.6 H9c2細胞分化 2.7 收取細胞與萃取蛋白 2.8 蛋白質定量 2.9 西方墨點法 2.10 免疫螢光染色 2.11 Transfection 2.12 Mature cardiomyocyte 數量之計數與量化 3. 結果 3.1 H9c2細胞分化形態觀察 13 3.2 H9c2細胞分化各種蛋白表現量 3.2.1 α-actinin 2 表現 13 3.2.2 Cardiac troponin T 表現 13 3.2.3 Palladin三個isoform表現 13 3.2.4 Nebulette 表現 14 3.3 H9c2分化時各種蛋白的表現位置 3.3.1 H9c2分化形態觀察 14 3.3.2 Sarcomeric α-actinin 於H9c2分化時的表現位置 14 3.3.3 cardiac troponin T於H9c2分化時的表現位置 14 3.3.4 Myosin heavy chain於H9c2分化時的表現位置 15 3.3.5 Palladin 90 kDa isoform於H9c2分化時的表現位置 15 3.3.6 Poly Palladin (200,140 kDa)於H9c2分化時的表現位置 15 3.3.7 Nebulette (Nebl)於H9c2分化時的表現位置 16 3.4 Palladin knockdown測試 16 3.5 Palladin knockdown 後H9c2分化形態觀察 16 3.6 Palladin 90 kDa knockdown 後各種蛋白的表現 3.6.1 Palladin 90 kDa knockdown後α-actinin 2表現 17 3.6.2 Palladin 90 kDa knockdown後cadiac troponin T表現 17 3.6.3 Palladin 90 kDa knockdown後palladin三個isoform表現 17 3.6.4 Palladin 90 kDa knockdown後nebulette 表現 18 3.7 Palladin 90 kDa knockdown後H9c2分化時各種蛋白的表現位置 3.7.1 Palladin 90 kDa knockdown後H9c2分化形態觀察 18 3.7.2 Palladin 90 kDa knockdown後sarcomeric α-actinin 於H9c2分化時的表現位置 18 3.7.3 Palladin 90 kDa knockdown後cardiac troponin T於H9c2分化時的表現位置 19 3.7.4 Palladin 90 kDa knockdown後myosin heavy chain於H9c2分化時的表現位置 19 3.7.5 Palladin 90 kDa knockdown後palladin 90 kDa isoform於H9c2分化時的表現位置 19 3.7.6 Palladin 90 kDa knockdown後poly palladin (200,140 kDa)於H9c2分化時的表現位置 20 3.7.7 Palladin 90 kDa knockdown後nebulette (Nebl)於H9c2分化時的表現位置 20 3.8 Palladin 90 kDa knockdown後mature cardiomyocyte數量的變化 21 4. 討論 4.1 心肌細胞於分化各時期之形態觀察 22 4.2 H9c2細胞分化時期分化marker蛋白(cardiomyogenic differentiation markers)的表達 23 4.3 H9c2細胞分化時期palladin 3個isoform蛋白(90~92 kDa、140 kDa、200 kDa)的表達 24 4.4 H9c2細胞分化時期nebulette蛋白的表達 25 4.5 進行免疫螢光染色前心肌細胞分化各時期之形態觀察 26 4.6 H9c2分化過程中分化marker蛋白(cardiomyogenic differentiation markers)表現位置 26 4.7 H9c2分化過程中palladin 3個isoform蛋白表現位置 27 4.8 H9c2分化過程中nebulette(Nebl)表現位置 27 4.9 Palladin knockdown測試 28 4.10 H9c2細胞進行negative control siRNA 與palladin si-RNA transfection使palladin knockdown後分化形態觀察 28 4.11 Palladin KD與CTL之marker蛋白(cardiomyogenic differentiation markers)的表達於H9c2分化期間表現量 29 4.12 Palladin 90 kDa KD palladin三個isoform表現 29 4.13 Palladin KD與CTL之nebulette (Nebl)蛋白於H9c2分化期間表現量 29 4.14 H9c2細胞進行negative control siRNA 與palladin si-RNA transfection使palladin knockdown後於免疫螢光染色前分化形態觀察 30 4.15 Palladin knockdown與negative control組分化marker蛋白(cardiomyogenic differentiation markers)蛋白表現位置 30 4.16 Palladin knockdown與negative control組palladin isoform表現位置 31 4.17 Palladin knockdown與negative control組nebulette表現位置 32 4.18 Palladin 90 kDa knockdown後 mature cardiomyocyte數量的變化 32 4.19 總結 33 5. 參考文獻 34 圖 圖目錄 圖一、H9c2細胞分化形態觀察 38 圖二、H9c2細胞分化形態觀察 39 圖三、α-actinin 2 蛋白於H9c2分化期間表現量 40 圖四、Cardiac troponin T蛋白於H9c2分化期間表現量 41 圖五、Palladin 90 kDa isoform蛋白於H9c2分化期間表現量 42 圖六、Palladin 140 kDa isoform蛋白於H9c2分化期間表現量 43 圖七、Palladin 200 kDa isoform蛋白於H9c2分化期間表現量 44 圖八、Nebulette蛋白於H9c2分化期間表現量 45 圖九、進行免疫螢光染色前H9c2分化形態觀察 46 圖十、H9c2分化形態觀察 47 圖十一、H9c2分化過程中sarcomeric α-actinin表現位置 48 圖十二、H9c2分化過程中sarcomeric α-actinin表現位置 49 圖十三、H9c2分化過程中cardiac troponin T表現位置 50 圖十四、H9c2分化過程中cardiac troponin T表現位置 51 圖十五、H9c2分化過程中myosin heavy chain表現位置 52 圖十六、H9c2分化過程中myosin heavy chain表現位置 53 圖十七、H9c2分化過程中palladin 90 kDa isoform表現位置 54 圖十八、H9c2分化過程中palladin 90 kDa isoform表現位置 55 圖十九、H9c2分化過程中poly palladin (200,140 kDa) isoform表現位置 56 圖二十、H9c2分化過程中poly palladin (200,140 kDa) isoform表現位置 57 圖二十一、H9c2分化過程中nebulette (Nebl)表現位置 58 圖二十二、H9c2分化過程中nebulette (Nebl)表現位置 59 圖二十三、Palladin knockdown測試 60 圖二十四、H9c2細胞進行negative control siRNA transfection後分化形態觀察 61 圖二十五、H9c2細胞進行negative control siRNA transfection後分化形態觀察 62 圖二十六、H9c2細胞進行si-RNA transfection使palladin knock down後分化形態觀察 63 圖二十七、H9c2細胞進行si-RNA transfection使palladin knock down後分化形態觀察 64 圖二十八、Palladin KD與CTL之α-actinin 2蛋白於H9c2分化期間表現量 65 圖二十九、Palladin KD與CTL之cardiac troponin T(cTnT)蛋白於H9c2分化期 66 圖三十、Palladin KD與CTL之palladin 90 kDa蛋白於H9c2分化期間表現量 67 圖三十一、Palladin KD與CTL之palladin 140 kDa蛋白於H9c2分化期間表現量 68 圖三十二、Palladin KD與CTL之palladin 200 kDa蛋白於H9c2分化期間表現量 69 圖三十三、Palladin KD與CTL之後nebulette (Nebl)蛋白於H9c2分化期間表現量 70 圖三十四、Palladin knockdown negative control 後H9c2分化形態觀察 71 圖三十五、Palladin knockdown negative control 後H9c2分化形態觀察 72 圖三十六、Palladin knockdown negative control 後H9c2分化形態觀察 73 圖三十七、Palladin knockdown negative control 後H9c2分化形態觀察 74 圖三十八、Palladin knockdown negative control sarcomeric α-actinin 蛋白表現位置 75 圖三十九、Palladin knockdown negative control sarcomeric α-actinin 蛋白表現位置 76 圖四十、Palladin knockdown sarcomeric α-actinin 蛋白表現位置 77 圖四十一、Palladin knockdown sarcomeric α-actinin 蛋白表現位置 78 圖四十二、Palladin knockdown negative control cardiac troponin T 蛋白表現位置 79 圖四十三、Palladin knockdown negative control cardiac troponin T 蛋白表現位置 80 圖四十四、Palladin knockdown cardiac troponin T蛋白表現位置 81 圖四十五、Palladin knockdown cardiac troponin T蛋白表現位置 82 圖四十六、Palladin knockdown negative control myosin heavy chain (MyHC)蛋白表現位置 83 圖四十七、Palladin knockdown negative control myosin heavy chain (MyHC)蛋白表現位置 84 圖四十八、Palladin knockdown Myosin heavy chain(MyHC)蛋白表現位置 85 圖四十九、Palladin knockdown Myosin heavy chain(MyHC)蛋白表現位置 86 圖五十、Palladin knockdown negative control palladin 90 kDa isoform蛋白表現位置 87 圖五十一、Palladin knockdown negative control palladin 90 kDa isoform蛋白表現位置 88 圖五十二、Palladin knockdown palladin 90 kDa isoform蛋白表現位置 89 圖五十三、Palladin knockdown palladin 90 kDa isoform蛋白表現位置 90 圖五十四、Palladin knockdown negative control palladin 140 kDa isoform蛋白表現位置 91 圖五十五、Palladin knockdown negative control palladin 140 kDa isoform蛋白表現位置 92 圖五十六、Palladin knockdown palladin 140 kDa isoform蛋白表現位置 93 圖五十七、Palladin knockdown palladin 140 kDa isoform蛋白表現位置 94 圖五十八、Palladin knockdown negative control nebulette 蛋白表現位置 95 圖五十九、Palladin knockdown negative control nebulette 蛋白表現位置 96 圖六十、Palladin knockdown nebulette蛋白表現位置 97 圖六十一、Palladin knockdown nebulette蛋白表現位置 98 圖六十二、Palladin knockdown negative control mature cardiomyocyte數量 99 圖六十三、Palladin knock down negative control mature cardiomyocyte數量 100 圖六十四、Palladin knockdown後 mature cardiomyocyte數量 101 圖六十五、Palladin knockdown後 mature cardiomyocyte數量 102 圖六十六、Palladin knockdown後與negative control組別mature cardiomyocyte數量量化圖 103  

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