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研究生:陳琬
研究生(外文):Wan Chen
論文名稱:探討游離輻射在生長期毛囊引起的萎縮性衰退期
論文名稱(外文):Investigation of ionizing radiation-induced dystrophic catagen in anagen hair follicle
指導教授:林頌然陳惠文陳惠文引用關係
指導教授(外文):Sung-Jan LinHuei-Wen Chen
口試委員:冀宏源
口試委員(外文):Hung-Yuan Chi
口試日期:2016-07-14
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:毒理學研究所
學門:醫藥衛生學門
學類:其他醫藥衛生學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:中文
論文頁數:77
中文關鍵詞:放射線治療游離輻射落髮毛囊毛囊生長週期衰退期
外文關鍵詞:RadiotherapyIonizing radiationHair lossHair follicleHair follicle growth cycleCatagen
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利用游離輻射進行放射治療是癌症療程中的一部份,雖然游離輻射能殺死癌細胞卻也會對病灶周圍的正常細胞造成傷害,引起的許多副作用嚴重地影響病人的生活品質。毛髮週期包括生長期、休止期與衰退期,由於生長期的毛囊細胞具有快速分裂特性,使毛囊成為容易受游離輻射傷害的器官之一,進而造成落髮,使病患不只承受療程帶來生理上的痛苦,更造成極大的心理壓力。然而游離輻射造成毛囊損傷與落髮的原因至今仍然不明,因此本研究的目的為探討游離輻射對生長期毛囊的影響及其造成落髮的相關機制。實驗利用四週齡的C57BL/6母鼠在第一個毛囊週期的生長期開始時,以7.5Gy的銫-137伽瑪射線照射其背部後觀察掉毛的情形並收集背部皮膚組織,並以出生後第39天,毛囊週期進入早期自發性衰退期的小鼠作為對照組。藉由H&E染色和免疫螢光染色分析游離輻射對毛囊的影響。實驗發現暴露7.5Gy游離輻射第五天後小鼠背部毛髮明顯脫落,且皮膚顏色由黑轉為粉紅色。組織切片染色結果指出毛囊結構在暴露游離輻射的第12小時後快速衰退,至第五天時毛囊已完全退縮至真皮層中,呈現與休止期類似的結構。利用γH2AX免疫螢光染色發現在暴露游離輻射的第6小時幾乎所有毛囊都表現嚴重的DNA損傷,而TUNEL assay也指出第12小時毛囊基質細胞大量死亡,以及第24小時毛囊內根鞘細胞大量死亡,同時毛囊球中表現BrdU細胞的數量也顯著減少,表示照射7.5Gy游離輻射抑制毛囊細胞分裂增殖,並在6小時內造成毛囊細胞嚴重的DNA 雙股斷裂,而受損的細胞在第12、24小時大量死亡,因此導致毛囊進入萎縮性衰退期。另一方面探討毛囊細胞對於游離輻射造成的DNA損傷修復情形,發現暴露游離輻射後RAD51主要分布於毛囊的毛囊球基質細胞部分,表示毛囊細胞透過同源重組(HR)修復機制修復基質細胞的DNA雙股斷裂,但隨後仍因毛囊受損過於嚴重而進入毛囊萎縮性衰退期。此外,實驗也比較毛囊正常衰退期與萎縮性衰退期之間細胞訊息傳遞途徑的變化,P-Smad2為TGF-β下游傳訊分子,參與細胞凋亡與生長期及衰退期的轉換,實驗發現在照射游離輻射的數小時內P-Smad2的表現受到抑制,直到第24小時之後P-Smad2才會明顯表現在毛囊中,暴露IR明顯影響毛囊P-Smad2的表現與分布,因此IR引起毛囊萎縮性衰退期的細胞凋亡機制可能與正常衰退期不同。本實驗利用B6小鼠建立模擬臨床上照射放射線造成的掉髮模式,並從不同角度探討正常毛囊衰退期與暴露游離輻射引起的萎縮性毛囊衰退期之間的差異。

Radiotherapy with ionizing radiation (IR) is widely used for cancer treatment. However, injury to normal surrounding tissue is inevitable resulting in various side effects. IR-induced alopecia is one of which extremely affects the patients’ life quality. Hair follicle (HF) undergoes repetitive cycles through growing (anagen), regressing (catagen) and resting (telogen) phases, called hair cycles. Due to the highly proliferative feature, anagen HF is one of the target organs vulnerable to IR, and IR-induced alopecia is often developed. However, how the IR damage to anagen HF and resulted in hair loss has been so far poor understood. Therefore, our work aims to explore the effect of IR injury to HFs and to identify the molecular mechanisms involved in the dystrophic change of HFs. In this study, C57BL/6 female mice were irradiated with gamma-rays (7.5Gy) from radioactive isotope Cs-137 (Caesium-137) on back skins when HFs entered into anagen. In addition, 39-day-old mice on early catagen of hair cycles were used as control group (0Gy). H&E staining and immunofluorescence staining were performed to analyze the morphological and biochemical changes after exposing to IR. Mice irradiated with IR showed bald dorsal region and the color of back skin changed from black to pink at day 5 post-irradiation. Histologically, 7.5Gy of IR caused apparent impairment in the structure of HFs, which became shorten and shrank rapidly into telogen-like structure from 12 hours to day 5 post-irradiation. Immunofluorescence staining by γH2AX indicated serious DNA damage on all of HF cells at 6 hours post- irradiation. Moreover, TUNEL assay showed severe apoptosis of matrix cells and extensive cell death in inner root sheath (IRS) as well as decomposed hair shaft (HS) at 12h and 24h post-irradiation. Number of BrdU positive cells in hair bulbs also decreased significantly after IR injury. These results represented that 7.5Gy of IR inhibited HF cell proliferation and caused severe DNA double strand breaks during first 6 hours, -apoptosis was subsequently induced from during 12 to 24 hours which lead to dystrophic catagen entry. On the other hand, DNA repair situation after IR exposure was also analyzed by immunofluorescence staining of Rad 51. Accordingly, the homologous recombination was involved in IR caused DNA DSB in HF matrix cells, but ultimately the repair failed and HFs entered into dystrophic catagen. Comparing of difference in cell signaling between normal catagen and dystrophic catagen, P-Smad2, a transducer in cell belongs to TGF-β signaling pathway involved in cell apoptosis and initiation of catagen, was found to express decreased level in few hours after exposing to IR but showed an increasing expression in HF after 24 hours post-irradiation. Therefore, this phenomenon may indicate the different mechanisms of cell death in IR induced dystrophic catagen. In summary, our study established an IR-induced hair loss model similar to clinical observation, and compared this dystrophic catagen with normal catagen in several aspects.

誌謝 i
中文摘要 ii
Abstract iv
第一章 緒論 2
1.1游離輻射的基本介紹 2
1.2游離輻射對生物體的傷害 3
I. 游離輻射對人體系統的影響 3
II. 游離輻射對細胞的影響 4
1.3 毛囊的基本介紹 7
1.3.1毛囊的結構 7
1.3.2毛囊的發展與生長週期 9
1.4游離輻射與毛囊 12
1.5臨床研究 13
1.6 化療導致的落髮 14
1.7 研究動機 16
第二章 實驗材料與方法 18
2.1動物實驗 18
2.1.1游離輻射對小鼠毛囊的傷害模式 18
2.1.2小鼠皮膚樣本處理-石蠟包埋與切片 18
2.1.3 他莫昔分(Tamoxifen)誘導Lgr5CreER小鼠tdTomato之表達 18
2.1.4小鼠皮膚樣本處理-冷凍包埋與切片 19
2.2 小鼠皮膚樣本染色 19
2.2.1蘇木精-伊紅染色(Hematoxylin & Eosin Stain, H&E stain) 19
2.2.2雙重免疫螢光染色 (Double immunofluorescence stain) 19
2.2.3末端脫氧核苷酸轉移酶脫氧尿苷三磷酸切口末端標記 (TUNEL Assay) 21
2.2.4 免疫組織化學染色 (Immunohistochemistry, IHC) 22
2.2.5 小鼠皮膚樣本冷凍切片染色 23
2.3 體外實驗 23
2.3.1 小鼠表皮角質細胞分離 23
第三章 實驗結果 25
3.1 暴露IR造成小鼠背部毛髮脫落 25
3.2 暴露IR造成小鼠毛囊受損 27
3.3.1 暴露IR造成毛囊細胞凋亡 29
3.3.2 暴露IR造成毛囊細胞凋亡 34
3.4 照射IR不會使免疫細胞遷移進入皮膚 37
3.5 照射IR抑制毛囊細胞增生以及破壞毛囊結構 41
3.6 照射IR造成毛囊細胞的DNA損傷 45
3.7 照射IR造成毛囊細胞的DNA損傷之修復 47
3.8 暴露IR對小鼠毛囊結構與生長週期細胞訊息傳遞的影響 49
3.9 暴露IR對小鼠生長週期的影響 55
3.10 暴露IR後對毛囊細胞的世系追踪(Linage tracing) 59
第四章 討論 62
第五章 結論與未來方向 67
參考文獻 70



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