核纖層蛋白A (Lamin A)是構成核膜的重要蛋白質，由於基因LMNA 1824 C > T 突變造成轉錄子剪接異常，最終產生早衰蛋白(Progerin)。於此我們實驗室建構一種藉由Pgk-Cre/ERT2操縱子控制下，誘導早衰蛋白表現的小鼠模型(Progerin/Pgk-Cre)，在小鼠成年後(7-8週大)，連續5天對其進行腹腔注射(IP)他莫昔芬(Tamoxifen)，誘使早衰蛋白表現，以下將小鼠模型表示為P-PgkCre+(帶有Cre 基因)、P+PgkCre-(帶有Progerin基因)及P+PgkCre+(帶有Progerin以及Cre 基因)。免疫組織化學(IHC)染色分析顯示，成年P+PgkCre+小鼠在誘導早衰蛋白表達後二個月，骨骼肌組織(Femoris)約53.52%的細胞中有早衰蛋白表現；蘇木精-伊紅(H&E)染色分析顯示，骨骼肌中有顯著的病理變化，與P+PgkCre-相比，P+PgkCre+中央核產生的頻率增加41.89% (p<0.0001)且肌核密度增加1.57倍(p=0.0093)，在與P+PgkCre-的平均肌纖維橫截面積大小2003.63 μm²相比，P+PgkCre+的平均肌纖維橫截面積為831.83 μm²，顯示整體有減少的趨勢(p=0.0004)；天狼星紅(Picro-sirus red)染色分析顯示，在P+PgkCre+中，膠原纖維蛋白佔整體骨骼肌橫截面積的比例達9.39%，與P+PgkCre- (1.63%)相比，提高7.76% (p=0.0009)。在RT-qPCR分析與纖維化相關的基因表現， P+PgkCre+的Tgf-、Col3a1、Eln及Col8a1皆受到上調，分別是P-PgkCre+的1.94倍(p=0.0003)、1.87倍(p=0.0011)、2.30倍(p=0.0319)及5.21倍(p=0.0005)，顯示骨骼肌中存在組織纖維化。在P+PgkCre+骨骼肌RNA定序(RNA-seq)的結果中，Ctss表現被上調22.5倍(p=6.16E-29)。先前研究顯示Ctss會對細胞外基質重塑產生影響，敲除Ctss後，膠原纖維蛋白佔P+PgkCre+骨骼肌橫截面積的比例為5.53%，與P+PgkCre+相比下降了3.86%(p=0.0136)，在RT-qPCR分析中，P+PgkCre+Ctss-/-的Col8a1表現被下調了1.98倍(p=0.0216)，顯示出P+PgkCre+小鼠在Ctss敲除後，可能透過下調Col8a1的表現，以此減輕P+PgkCre+骨骼肌纖維化的產生。因此本研究顯示早衰蛋白表現會誘導成年骨骼肌的退化，並與Ctss之間存在一定的功能性連結。

Lamin A is an important factor constituting the nuclear membrane. Progerin is a truncated toxic form of prelamin A resulted from aberrant splicing of LMNA 1824C > T mutant gene. Here we created a mouse model that inducibly overexpressed with progerin under the control of Pgk-Cre/ERT2 operon. Following the transition to adulthood, mice were intraperitoneally given with tamoxifen for 5 consecutive days. Immunohistochemical analysis revealed that progerin is expressed in approximately 53.52% of the cells in skeletal muscle (femoris) after two months of the induction. Hematoxylin and Eosin staining analysis showed significant pathologic alterations in the skeletal muscle. The frequency of central nuclei has increased by 41.89% (p<0.0001) and the density of nucleus increased by 1.57 times (p<0.0001) in the skeletal muscle of P+PgkCre+ (knockin progerin and Cre) mice compared to P+PgkCre- (knockin only progerin) mice. The cross-sectional area of progerin-expressing myocytes was significantly reduced (831.83 μm²) compared to P+PgkCre- (2003.63 µm²). Picro-sirus red staining analysis revealed that in the skeletal muscle of P+PgkCre+ mice, collagen fiber area ratio reaches 9.39%, which is a 7.76% increase compared to P+PgkCre- (1.6%, p=0.0009). Using RT-qPCR to analyze expression of genes related to fibrosis, we found Tgf-β1, Col3a1, Eln, and Col8a1 in P+PgkCre+ mice were respectively upregulated by 1.94-fold (p=0.0003), 1.87-fold (p=0.0011), 2.30-fold (p=0.0319), and 5.21-fold (p=0.0005) compared to P-PgkCre+ (knockin only Cre) mice. The above results indicate the presence of fibrosis in the skeletal muscle. Using next-generation RNA sequencing, we found the expression of cathepsin S (Ctss) was significantly upregulated in the skeletal muscle. Ctss is known to have a role in extracellular matrix remodeling. In this study, the collagen fiber area ratio in the skeletal muscle of P+PgkCre+Ctss-/- mice was 5.53%, which is a 3.86% decrease (p=0.0136) compared to P+PgkCre+ mice (9.39%). The expression of Col8a1 was reduced by 1.98-fold (p=0.0216) in P+PgkCre+Ctss-/- compared to P+PgkCre+ mice. These results suggest that Ctss contributes to skeletal muscle fibrosis in P+PgkCre+ mice accompanying with overexpression of Col8a1. In conclusion, this study shows a functional link between Ctss and progerin-induced skeletal muscle degeneration.

目錄

摘要 I
Abstract III
致謝 V
目錄 VI
圖表目錄 XI
附錄目錄 XII
縮寫與全名對照表 XIII
壹、前言 1
1-1 背景 1

1-2 核纖層蛋白(Nuclear lamina) 1
1-2-1 基本介紹 1
1-2-2 LMNA與核纖層蛋白A/C (Lamin A/C) 2
1-2-3 LMNA突變與其相關疾病 2

1-3 早衰蛋白(Progerin) 3
1-3-1 基本介紹 3
1-3-2 早衰蛋白與HGPS 3
1-3-3 早衰症與正常老化 4

1-4 骨骼肌 4
1-4-1 基本介紹 4
1-4-2 骨骼肌中央核 5
1-4-3 骨骼肌中央核與相關疾病 5
1-4-4 骨骼肌與細胞外基質(ECM) 5
1-4-5 骨骼肌的修復與再生 6

1-5 組織纖維化 6

1-6 組織蛋白酶(Cathepsin) 7
1-6-1 基本介紹 7
1-6-2 胱氨酸蛋白酶(Cysteine cathepsin protease) 7
1-6-3 組織蛋白酶S(Cathepsin S, Ctss) 8
1-6-4 組織蛋白酶S與相關疾病 9
1-6-5 組織蛋白酶S抑制劑 9

1-7 小鼠模型選用 10

1-8 研究動機與目的 10


貳、材料與實驗方法 11
2-1 實驗材料 11
2-1-1 實驗動物 11
2-1-1-1 Ctss knockout小鼠 11
2-1-1-2 Progerin knockin小鼠 12
2-1-1-3 Pgk1-RFP,-Cre/ERT2小鼠 12
2-1-2 實驗試劑及藥品 13

2-2 實驗方法 14
2-2-1 Polymerase chain reaction (PCR) 14
2-2-2 限制酶切割 15
2-2-3 凝膠電泳 15
2-2-4 辨識基因型(Genotyping) 16
2-2-5 動物組織處理 17
2-2-6 組織切片及染色 17
2-2-6-1 備製組織切片 17
2-2-6-2 蘇木精-伊紅染色(Hematoxylin and Eosin Stain) 18
2-2-6-3 免疫組織化學染色(Immunohistochemistry) 18
2-2-6-4 天狼星紅染色法(Picro-sirius Red Stain) 19
2-2-7 動物組織RNA樣本萃取、純化及定量 20
2-2-7-1 利用TRIzol萃取組織RNA 20
2-2-7-2 利用Column萃取組織RNA -進行再純化 20
2-2-7-3 RNA定量 21
2-2-8 RT-qPCR 21
2-2-8-1 反轉錄(Reverse Transcription, RT) 21
2-2-8-2 qPCR 22
2-2-9 蛋白質樣本備製 23
2-2-10 西方墨點法(Western Blot) 24
2-2-10-1 SDS-PAGE 24
2-2-10-2 SDS-polyacrylamide電泳 24
2-2-10-3 轉漬(Transfer) 25
2-2-10-4 封閉(Blocking)、一級抗體(1° Antibody)及二級抗體(2° Antibody) 26
2-2-10-5 抗體辨識顯影成像 26
2-2-11 統計分析 27

參、結果 28
3-1 Progerin/Pgk-Cre小鼠模型及動物實驗設計 28

3-2 Tamoxifen誘導早衰蛋白表現後，在組織中各時期的表現率，並在骨骼肌組織中具有顯著性差異 28

3-3 早衰蛋白導致成年小鼠的皮下脂肪層及皮下肌肉層厚度減少 29

3-4 誘導早衰蛋白表現二個月後，導致成年小鼠骨骼肌中產生大量中央核且伴隨著肌核密度的增加 30

3-5 早衰蛋白導致成年小鼠骨骼肌的肌纖維橫截面積縮減及組織纖維化產生 31

3-6 成年早衰小鼠骨骼肌中，Tgf-1、Col3a1、Eln及Col8a1表現量上調 32

3-7 RNA-seq結果顯示Cysteine cathepsin家族成員在P+PgkCre+小鼠的Femoris中被顯著性上調 33

3-8 早衰蛋白導致成年小鼠骨骼肌的Ctss及Ctss表現上調 33

3-9 Ctss敲除的早衰小鼠獲取方式及小鼠體重變化 34

3-10 敲除Ctss降低成年早衰小鼠骨骼肌中央核頻率、增加肌纖維橫截面積並減輕纖維化 35

3-11 成年早衰小鼠在Ctss敲除後，Col8a1的表現量被下調 36

肆、討論 37
伍、圖表 43
陸、參考文獻 63
柒、附錄 75





圖表目錄

表一、 RNA-seq結果，在P+PgkCre+小鼠的Femoris中，Cysteine cathepsin家族成員皆被顯著性上調 43
圖一、 Progerin/Pgk-Cre小鼠模型實驗設計及各基因型小鼠體重變化 44
圖二、 Tamoxifen誘導早衰蛋白表現後，在組織中各時期的表現率，並在骨骼肌組織中具有顯著性差異 46
圖三、 早衰蛋白導致成年小鼠的皮下脂肪層及皮下肌肉層厚度減少 48
圖四、 誘導早衰蛋白表現二個月後，導致成年小鼠骨骼肌中產生大量中央核且伴隨著肌核密度的增加 50
圖五、 早衰蛋白導致成年小鼠骨骼肌的肌纖維橫截面積縮減及組織纖維化產生 53
圖六、 成年早衰小鼠骨骼肌中，Tgf-1、Col3a1、Eln及Col8a1的表現量上調 54
圖七、 早衰蛋白導致成年小鼠骨骼肌的Ctss及Ctss表現上調 56
圖八、 Progerin/Pgk-Cre/Ctss-/-各基因型小鼠體重變化 57
圖九、 敲除Ctss降低成年早衰小鼠骨骼肌中央核頻率、增加肌纖維橫截面積並減輕纖維化 60
圖十、 成年早衰小鼠在Ctss敲除後，Col8a1的表現量被下調 62






附錄目錄

附錄一、 免疫組織化學染色分析，各時期早衰蛋白表現於十種組織細胞 75
附錄二、 誘導早衰蛋白表現後二個月，早衰小鼠九種組織中Ctss的表現量 79
附錄三、 膠原纖維量化統計方法示意圖 81
附錄四、 誘導早衰蛋白表現後二個月，早衰小鼠的Femoris中Col1a1及Col1a2表現量 82
附錄五、 小鼠qPCR引子序列表 83

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