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研究生:黃承鋒
研究生(外文):Chen-Fong Huang
論文名稱:探討藉由活化PPARγ對於神經細胞(N2A)以及神經退化性疾病的影響
論文名稱(外文):PPARγ activation in N2A cells and neurodegenerative disease
指導教授:謝坤叡江明璋
指導教授(外文):Kun-Ruey ShiehMing-Chang Chiang
口試日期:2011-07-11
學位類別:碩士
校院名稱:慈濟大學
系所名稱:生理暨解剖醫學碩士班
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2011
畢業學年度:99
語文別:中文
論文頁數:58
中文關鍵詞:漢丁頓舞蹈症
外文關鍵詞:Huntington's disease's
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研究證實PPARγ 的增效劑在體外實驗的模型中可以減少經由神經毒性產生導致的神經細胞損失,而在體內實驗的模型中可以減少由阿茲海默氏症、帕金森氏症和肌萎縮性脊髓側索硬化症導致的神經細胞損失。在本研究中,首先給予N2A 細胞三天和五十六天的rosiglitazone 後去觀察N2A 細胞的型態以及是否有保護神經細胞的效果。之後,我們去觀察PPARγ 在神經退化性疾病中扮演什麼樣的角色,在本實驗中我們使用漢丁頓舞蹈症轉基因小鼠模型。漢丁頓舞蹈症是一種體染色體顯性遺傳的神經退化性疾病,導因是在Htt gene 的exon 1 上會有CAG三核甘酸異常重複且延長的現象,漢丁頓舞蹈症是由於大腦的神經元持續退化導致神經系統信號傳遞的部分地區嚴重功能障礙。漢丁頓舞蹈症會攻擊大腦的神經元特別是小腦和海馬迴,在漢丁頓舞蹈症小鼠的大腦中,PPARγ 和粒線體相關的基因 (PGC-1α, NRF-1, NRF-2 and Tfam) 的基因表現量是降低的,而經由給予TZD 的處理後PPARγ 和粒線體相關的基因 (PGC-1α, NRF-1, NRF-2 and Tfam)的基因表現量有回復的情形出現,在漢丁頓舞蹈症小鼠中的Bcl-2, HSP-60 和HSP-70 蛋白質表現量是下降的,利用TZD 處理後同樣會有回復的情形。因此本實驗探討在漢丁頓舞蹈症小鼠腦中活化PPARγ 對於粒線體的功能影響,這可能是一個在漢丁頓舞蹈症的症狀中改善腦損傷的重要治療方法。
It has been demonstrated that PPARγ agonists reduce neuronal cell loss in in vitro
models of neurotoxicity and in in vivo models of Alzheimer's Disease, Parkinson’s
disease and amyotrophic lateral sclerosis. In this study, we treat rosiglitazone three
days in the first and then we treat rosiglitazone fifty-six days to investigate the neuron
cells’ morphology and whether it has neuroprotective effects. At last, we investigate
what PPARγ plays the neuroprotective role in neurodegenerative disease. In this study,
we also use Huntington's disease's (HD) transgenic mice model. HD is an autosomal
dominant hereditary neurodegenerative disease caused by a CAG trinucleotide repeats
exceptional expansion of exon 1 of the Huntingtin (Htt) gene. HD is due to brain
neurons continued to degenerate, resulting in nervous system signaling some areas
serious dysfunction. HD will attack the brain neurons, also particularly the cerebellum
and hippocampus specific. In the brain of the HD mice, the baseline levels of PPARγ
and mitochondrial genes (PGC-1α, NRF-1, NRF-2 and Tfam) mRNA were reduced
and then we use TZD treatment, PPARγ and mitochondrial genes (PGC-1α, NRF-1,
NRF-2 and Tfam) mRNA were recoverd. The baseline levels of Bcl-2, HSP-60,
HSP-70 proteins were also reduced in HD mice. We use TZD treatment also recoverd
in HD mice. Therefore, this study investigate the activation of PPARγ in HD mice
brain of mitochondrial function, which may be an important therapeutic approach to
improve brain damage in HD symptoms.
目錄 (Table of Contents)
致謝 I
Abstract II
中文摘要 III
目錄 IV
圖、表目錄 VI
第一章 緒論 1
第一節 PPARγ (peroxisome proliferator-activated receptor gamma) 1
第二節 漢丁頓舞蹈症 (Huntington’s disease,HD) 3
第三節 HD 誘發中樞神經 (CNS) 損害 5
第四節 HD對小腦 (Cerebellum) 與海馬迴 (Hippocampus) 的影響 6
第五節 HD對PPARγ與粒線體的影響 7
第六節 HD 與Ubiquitin-proteasome system (UPS) 8
第二章 實驗材料與方法 10
第一節 細胞培養 (Cell Culture) 10
第二節 細胞活性分析法 11
第三節 實驗動物 11
第四節 蛋白質定量 (Protein Assay 12
第五節 西方墨點法(Western Blot) 13
第六節 定量聚合酶連鎖反應 14
第三章 實驗結果 16
第一節 觀察給予RGZ短時間處理 (3 天) 以及長時間處理 (56 天) 後,N2A細胞所產生的變化 16
第二節 在長期給予TZD 處理後對R6/2 小鼠中Cerebellum 與Hippocampus的變化 18
第四章 討論 21
第一節 給予N2A 細胞RGZ 短期以及長期處理後,對於細胞產生突觸外生的情形 21
第二節 N2A 細胞在短期和長期給予RGZ 下的生長狀況以及在serum 或者serum free 狀態下存活的情形 21
第三節 在短期和長期給予RGZ 以及在serum 或者serum free 的情況下,對於N2A 細胞中Bcl-2、20S proteasome 蛋白質的變化 22
第四節 在長期給予TZD 處理後對R6/2 小鼠中Cerebellum 與Hippocampus中的PPARγ 以及PGC-1? 表現量的影響 23
第五節 在長期給予TZD 處理後對R6/2 小鼠中Cerebellum 與Hippocampus中的粒線體相關基因的影響 24
第六節 在長期給予TZD 處理後對R6/2 小鼠中Cerebellum 的保護作用 25
第五章 未來展望 27
第六章 圖、表及說明 28
第七章 參考文獻 48

圖、表目錄 (List of Tables and Figures)
表目錄
表 1. 定量RT-PCR的primers 29
表 2. 給予N2A 細胞不同濃度的Rosiglitazone (RGZ) 所引起突觸外生的數量以及長度 30

圖目錄
圖 1. 觀察給予不同濃度的RGZ處理3天後,對於N2A細胞型態的變化 31
圖 2. 觀察給予不同濃度的RGZ處理56天後,對於N2A細胞型態的變化 32
圖 3. 觀察給予不同濃度的RGZ處理3天後,對於N2A細胞生長情形的變化 33
圖 4. 觀察給予不同濃度的RGZ處理3天後再給予無血清狀態維持兩天,對於N2A細胞生長情形的變化 34
圖 5. 觀察給予不同濃度的RGZ處理56天後,對於N2A細胞生長情形的變化 35
圖 6. 觀察給予不同濃度的RGZ處理56天後再給予無血清狀態維持兩天,對於N2A細胞生長情形的變化 36
圖 7. 在短期給予RGZ處理後對於N2A細胞中Bcl-2和20S proteasome蛋白質表現量的影響 37
圖 8. 在短期給予RGZ處理後再給予無血清狀態維持兩天,對於N2A細胞中Bcl-2和20S proteasome蛋白質表現量的影響 38
圖 9. 在長期給予RGZ處理後對於N2A細胞中Bcl-2和20S proteasome蛋白質表現量的影響 39
圖 10. 在長期給予RGZ處理後再給予無血清狀態維持兩天,對於N2A細胞中Bcl-2和20S proteasome蛋白質表現量的影響 40
圖 11. 經由TZD長期處理後在R6/2小鼠小腦和海馬迴組織中PPARγ基因表現量的情形 41
圖 12. 經由TZD長期處理後在R6/2小鼠小腦和海馬迴組織中PGC-1?扆穧]表現量的情形 42
圖 13. 經由TZD長期處理後在R6/2小鼠小腦和海馬迴組織中NRF-1基因表現量的情形 43
圖 14. 經由TZD長期處理後在R6/2小鼠小腦和海馬迴組織中NRF-2基因表現量的情形 44
圖 15. 經由TZD長期處理後在R6/2小鼠小腦和海馬迴組織中Tfam基因表現量的情形 45
圖 16. 在長期給予TZD處理後,對於R6/2小鼠小腦和海馬迴組織中Bcl-2和20Sproteasome蛋白質表現量的情形 46
圖 17. 在長期給予TZD處理後,對於R6/2小鼠小腦和海馬迴組織中HSP-60和HSP-70蛋白質表現量的情形 47
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