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標題: | mTOR分子傳遞路徑在受游離輻射傷害的小鼠毛囊之修復機轉中的角色 The role of mTOR signaling in hair follicle repair in response to ionizing radiation damage in mice |
作者: | Ting-Han Chien 簡廷翰 |
指導教授: | 林頌然(Sung-Jan Lin) |
關鍵字: | 放射治療,落髮,mTOR訊息路徑,雷帕黴素,DNA傷害反應, radiotherapy,alopecia,mTOR signaling,rapamycin,DNA damage response, |
出版年 : | 2015 |
學位: | 碩士 |
摘要: | 放射治療是近年來常用的癌症療法之一,其特色在於可藉由具穿透性的游離輻射來對體內的病灶進行非侵入性的治療處置。然而,游離輻射會同時對病灶附近的正常組織造成傷害,因而產生對應的副作用症狀,其中,最明顯的副作用為落髮,會造成病人的觀感不佳、生活品質下降。如何減緩放療後的落髮症狀,是重要的研究課題之一。mTOR訊息傳遞路徑是細胞重要的接收營養、壓力訊號的分子訊息中樞之一,已知在皮膚及毛髮的修復過程中扮演重要的角色。然而,遭受游離輻射傷害時,在mTOR被抑制的情況下,有些組織反而增強對抗輻射的能力。我們想知道,對於毛髮受輻射傷害後,在mTOR被抑制時的傷害表現又是如何?
本研究使用32天大的雌性C57BL/6黑毛小鼠作為動物實驗對象,在施打mTOR抑制劑雷帕黴素(rapamycin)後施以全身游離輻射照射,而後持續施打雷帕黴素觀察至毛髮衰退期(telogen)。實驗結果發現,在4Gy以上的劑量下,施打雷帕黴素的小鼠在第5天開始有明顯的掉毛,而控制組則無。從背皮組織切片的H&E染色可以發現施打雷帕黴素的小鼠的毛囊,在第3天有較嚴重的變形,之後的修復狀況也較控制組差。免疫螢光染色的結果發現,施打雷帕黴素的小鼠其毛囊球部的基質細胞進行分裂的細胞較少,但自我凋亡的細胞數量則無差異;毛囊微結構染色發現施打雷帕黴素的小鼠毛囊,在第4天修復後的髮幹內心IRS及毛皮質部的結構並不正常。從細胞週期相關的調控蛋白的染色結果,本研究發現mTOR訊息路徑受抑制時,毛囊細胞受游離輻射影響而產生細胞週期停滯的現象,其持續時間會延長,間接影響到基質細胞進行增生、參與毛囊修復的能力。mTOR訊息路徑的抑制,也導致毛囊細胞在輻射傷害早期出現較多的DNA傷害。最後,本研究探討了與毛囊生長期生長調控相關的Wnt訊息路徑,並發現受輻射傷害的毛囊的修復後期,可能是由Wnt訊息路徑主導,而mTOR訊息路徑的抑制可能導致Wnt訊息路徑的活性受到影響,而造成修復後期的毛囊修復不佳的結果。 本研究證實了mTOR訊息路徑於受輻射傷害毛囊的修復機制中的重要性。 Radiotherapy is one of the commonly used in cancer treatment. By use of ionizing radiation (IR), radiotherapy can kill cancer cells inside our bodies. However, IR can also cause damage to adjacent healthy tissues, resulting in various acute or chronic side effects. One of the most annoying side effects to is IR-induced alopecia, which is often seen after radiotherapy for head and neck neoplasm. There is currently no efficient treatment for IR-induced alopecia. mTOR signaling is a well-known signaling pathway responding to growth factors, nutrients, oxygen and energy level. mTOR signaling has been reported to be involved in regeneration processes in skin and hair. Whether mTOR can be a possible molecular target to prevent IR-induced alopecia is unknown. Here we explored this possibility. Thirty two-day-old C57BL/6 mice were given mTOR inhibitor rapamycin and then exposed to IR. At 4 Gy of IR, inhibition of mTOR signaling resulted in more severe alopecia in 5 days. Histological analysis showed more severe hair follicle shortening and dystrophy. The self-repair for hair dystrophy was impaired. Further analysis showed that inhibition of mTOR signaling did not increased apoptosis but reduced cell proliferation with increased cell cycle arrest. In addition, differentiation of hair follicle was also compromised. Increased DNA damage intense at early time points after IR exposure was also observed. For molecular signaling, we found mTOR inhibition might inhibit the repair process by affecting Wnt signaling activity. This research demonstrated the possible role of mTOR signaling in hair follicle repair in response to IR. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/52518 |
全文授權: | 有償授權 |
顯示於系所單位: | 醫學工程學研究所 |
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