跳到主要內容

臺灣博碩士論文加值系統

(18.97.14.81) 您好!臺灣時間:2025/02/10 23:59
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:游登輝
研究生(外文):Deng-Hwuei You
論文名稱:利用大鼠雙毒素模型探討人類脂肪幹細胞治療多發性系統退化症之可行性
論文名稱(外文):Investigating the Feasibility of Transplanting Adipose-Derived Stem Cells to Treat Multiple System Atrophy Using a Double Toxin-Induced Rat Model
指導教授:邱紫文邱紫文引用關係
指導教授(外文):Tzyy-Wen Chiou
學位類別:碩士
校院名稱:國立東華大學
系所名稱:生命科學系
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
論文頁數:71
中文關鍵詞:脂肪幹細胞多發性系統退化症細胞治療
外文關鍵詞:Adipose-derived stem cellsMultiple system atrophyCell therapy
相關次數:
  • 被引用被引用:0
  • 點閱點閱:289
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
摘要
  多發性系統退化症為一種神經退化性疾病,因症狀主要呈現兩種以上的中樞神經系統退化而得名。多發性系統退化症疾病進程快速且致死率高,目前臨床上尚無有效治療之手段,因此研究新的治療方式是一項刻不容緩的主題。脂肪幹細胞為一種間質幹細胞,因其取得容易,且具有分化以及分泌神經營養因子的功能,可幫助神經元生長與再生,於神經退化性疾病之治療潛力備受矚目。本實驗以大鼠單側腦雙毒素雙病變的誘導方式,以六-羥基多巴胺破壞黑質體神經元,再以喹啉酸破壞紋狀體神經元,誘導紋狀體與黑質體退化,使多巴胺神經徑路產生障礙,藉以模擬P型多發性系統退化症之病徵 (包含類帕金森症狀以及L-Dopa不敏感之症狀)。完成誘導後,將多發性系統退化症大鼠模型隨機分為三組,並依據組別於患側紋狀體移植細胞,動物分組如下:劑量一組:移植3.4x106之人類脂肪幹細胞;劑量二組:移植3.4x105之人類脂肪幹細胞;Vehicle組:施打磷酸鹽緩衝生理鹽水。試驗結果顯示,經細胞移植後較低劑量組於第14天可觀察到前肢踏步能力與轉棒平衡能力顯著改善;紋狀體之中型多棘神經元明顯再生;然而,高劑量組動物行為之恢復與紋狀體神經元再生效力不如低劑量組。另外,利用專一性抗體人類粒線體特異蛋白進行移植細胞之追蹤,發現移植之人類脂肪幹細胞可於大腦紋狀體存活至少28天。同時,本研究亦發現細胞移植組別在大腦紋狀體處具有較高之神經營養因子 GDNF (Glial cell-derived neurotrophic factor)表現,因此幫助紋狀體重建。此一現象並未於黑質體區域發現,可能與試驗中觀察到細胞移植後多巴胺神經元修復較少之現象有相關性。總之,本研究成功建立了雙毒素誘導之多發性系統退化症動物,並以此模型驗證了人類脂肪幹細胞移植做為多發性系統退化症治療手段之可行性。人類脂肪幹細胞移植幫助了移植部位之神經營養因子分泌,進一步修復紋狀體多巴胺受體神經元,達到改善多發性系統退化症病徵之效用,說明人類脂肪幹細胞治療多發性系統退化症具有相當的潛力。

關鍵字:脂肪幹細胞、多發性系統退化症、細胞治療。
Abstract
  Multiple system atrophy (MSA) is a rare neurodegenerative disorder caused by progressive degeneration of neurons in two or more parts of the brain, including substantia nigra, striatum, cerebellum, and so on. Up to now, there is no effective therapeutic strategy for MSA in clinical practice. The patients with MSA have a rapid progress and high mortality after the onset of symptoms. Therefore, the need for a new therapeutic strategy for MSA is urgent. Due to their availability, differentiation potential and the neurotrophic factor secretion ability, adipose-derived stem cells (ADSCs) raised much attention on the treatment for neurodegenerative disease. In this study, we established a unilateral partial double toxin- and double lesion-induced rat model, which can mimic features of the Parkinsonism and L-dopa insensitive symptoms in the brains of Parkinsonism-MSA. Using the toxins, the functions of the dopaminergic pathway in striatum and substantia nigra were injured. Therefore, we used 6-hydroxydopamine to damage the nigral neurons, and then used quinolinic acid to damage the striatal neurons. After the toxin induction, we transplanted human ADSCs to the ipsilateral striatum of Parkinsonism-MSA rats to assess the therapeutic effect of human ADSCs therapy. Three groups, including ADSCs with different cell doses (3.4x105 or 3.4x106) and vehicle (PBS) were examined. It was found that the lower dose ADSCs therapy led to improvement behavior performance in stepping test, rotarod test and regeneration of medium spiny neurons in the striatum in Parkinsonism-MSA rats. The higher dose group did not result in better result. Accordingly, in vivo tracing result revealed that ADSCs could survive for more than 28 days in the ipsilateral striatum. Moreover, ADSCs could produce and secret glial cell-derived neurotrophic factor (GDNF), which could assist the neuron reconstruction in striatum. However, it was found that ADSCs therapy have limited effect on the substantia nigra. In conclusion, the transplantation of human ADSCs could restore the striatal dopamine receptor neurons and improve animal behavior. Thus, ADSCs have considerable potential for MSA treatment.

Key words:adipose-derived stem cells;multiple system atrophy;cell therapy
目錄
一、研究背景及目的 1
二、文獻回顧 3
2.1 多發性系統退化症 3
2.2 α-突觸核蛋白 5
2.3 多巴胺神經徑路 8
2.4 多巴胺受體 9
2.5 紋狀體與黑質體退化 11
2.6 老鼠動物模型 13
2.7 多發性系統退化症治療策略 16
2.8 間質幹細胞移植治療神經退化性疾病 18
2.9 脂肪幹細胞 19
三、研究方法 21
3.1 實驗設計原理 21
3.1.1 雙毒素雙病變大鼠模型 21
3.1.2 動物行為測試 23
3.1.3 免疫組織化學染色 25
3.2 實驗方法 27
3.2.1 脂肪幹細胞培養 28
3.2.2 實驗動物飼養 29
3.2.3 大鼠腦立體定位微注射手術 29
3.2.4 動物行為測試 31
3.2.4.1 阿普嗎啡誘導旋轉測試 31
3.2.4.2 前肢踏步能力測試 32
3.2.4.3 轉棒平衡能力測試 32
3.2.5 組織學 33
3.2.5.1 組織取樣 33
3.2.5.2 組織封埋 33
3.2.5.3 組織切片 34
3.2.5.4 免疫組織化學染色 34
四、實驗結果 37
4.1 大鼠紋狀體與黑質體退化之多發性系統退化症模型篩選 37
4.1.1 六-羥基多巴胺與喹啉酸誘導後阿普嗎啡誘導旋轉測試之比較 37
4.1.2 前肢踏步能力測試與L-Dopa給藥反應 37
4.2 脂肪幹細胞移植後之評估 42
4.2.1 前肢踏步能力測試 42
4.2.2 轉棒平衡能力測試 44
4.2.3 組織學染色 46
4.2.3.1 酪氨酸羥化酶免疫組織化學染色 46
4.2.3.2 DARPP-32免疫組織化學染色 50
4.2.3.3 人類粒線體特異蛋白免疫組織化學染色 53
4.2.3.4 GDNF免疫組織化學染色 56
五、討論 59
六、結論 63
七、參考文獻 65
參考文獻:
Alimperti, S., Lei, P., Wen, Y., Tian, J., Campbell, A. M., & Andreadis, S. T. (2014). Serum-free spheroid suspension culture maintains mesenchymal stem cell proliferation and differentiation potential. Biotechnol Prog, 30(4), 974-983. doi:10.1002/btpr.1904
Amalric, M., & Koob, G. F. (1987). Depletion of dopamine in the caudate nucleus but not in nucleus accumbens impairs reaction-time performance in rats. J Neurosci, 7(7), 2129-2134.
Bellucci, A., Navarria, L., Zaltieri, M., Falarti, E., Bodei, S., Sigala, S., . . . Spano, P. (2011). Induction of the unfolded protein response by alpha-synuclein in experimental models of Parkinson's disease. J Neurochem, 116(4), 588-605. doi:10.1111/j.1471-4159.2010.07143.x
Ben-Hur, T., Fainstein, N., & Nishri, Y. (2013). Cell-based reparative therapies for multiple sclerosis. Curr Neurol Neurosci Rep, 13(11), 397. doi:10.1007/s11910-013-0397-5
Biaggioni, I., Freeman, R., Mathias, C. J., Low, P., Hewitt, L. A., Kaufmann, H., & Droxidopa, I. (2015). Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa. Hypertension, 65(1), 101-107. doi:10.1161/HYPERTENSIONAHA.114.04035
Blum, D., Torch, S., Lambeng, N., Nissou, M., Benabid, A. L., Sadoul, R., & Verna, J. M. (2001). Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson's disease. Prog Neurobiol, 65(2), 135-172.
Bonini, N. M., & Giasson, B. I. (2005). Snaring the function of alpha-synuclein. Cell, 123(3), 359-361. doi:10.1016/j.cell.2005.10.017
Braak, H., Del Tredici, K., Rub, U., de Vos, R. A., Jansen Steur, E. N., & Braak, E. (2003). Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging, 24(2), 197-211.
Burre, J., Sharma, M., Tsetsenis, T., Buchman, V., Etherton, M. R., & Sudhof, T. C. (2010). Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science, 329(5999), 1663-1667. doi:10.1126/science.1195227
d'Anglemont de Tassigny, X., Pascual, A., & Lopez-Barneo, J. (2015). GDNF-based therapies, GDNF-producing interneurons, and trophic support of the dopaminergic nigrostriatal pathway. Implications for Parkinson's disease. Front Neuroanat, 9, 10. doi:10.3389/fnana.2015.00010
Dang, S., Xu, H., Xu, C., Cai, W., Li, Q., Cheng, Y., . . . Zhang, Y. (2014). Autophagy regulates the therapeutic potential of mesenchymal stem cells in experimental autoimmune encephalomyelitis. Autophagy, 10(7), 1301-1315. doi:10.4161/auto.28771
Danielyan, L., Schafer, R., von Ameln-Mayerhofer, A., Bernhard, F., Verleysdonk, S., Buadze, M., . . . Frey, W. H., 2nd. (2011). Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease. Rejuvenation Res, 14(1), 3-16. doi:10.1089/rej.2010.1130
Darios, F., Ruiperez, V., Lopez, I., Villanueva, J., Gutierrez, L. M., & Davletov, B. (2010). Alpha-synuclein sequesters arachidonic acid to modulate SNARE-mediated exocytosis. EMBO Rep, 11(7), 528-533. doi:10.1038/embor.2010.66
de Munter, J. P., Lee, C., & Wolters, E. (2013). Cell based therapy in Parkinsonism. Transl Neurodegener, 2(1), 13. doi:10.1186/2047-9158-2-13
de Oliveira, G. L., de Lima, K. W., Colombini, A. M., Pinheiro, D. G., Panepucci, R. A., Palma, P. V., . . . Malmegrim, K. C. (2015). Bone marrow mesenchymal stromal cells isolated from multiple sclerosis patients have distinct gene expression profile and decreased suppressive function compared with healthy counterparts. Cell Transplant, 24(2), 151-165. doi:10.3727/096368913X675142
DeFrance, J. F., Sikes, R. W., & Chronister, R. B. (1985). Dopamine action in the nucleus accumbens. J Neurophysiol, 54(6), 1568-1577.
Ding, D. C., Shyu, W. C., & Lin, S. Z. (2011). Mesenchymal stem cells. Cell Transplant, 20(1), 5-14. doi:10.3727/096368910x
Dong, Z., Luo, L., Liao, Y., Zhang, Y., Gao, J., Ogawa, R., . . . Lu, F. (2014). In vivo injectable human adipose tissue regeneration by adipose-derived stem cells isolated from the fluid portion of liposuction aspirates. Tissue Cell, 46(3), 178-184. doi:10.1016/j.tice.2014.04.001
Emmanouilidou, E., Stefanis, L., & Vekrellis, K. (2010). Cell-produced alpha-synuclein oligomers are targeted to, and impair, the 26S proteasome. Neurobiol Aging, 31(6), 953-968. doi:10.1016/j.neurobiolaging.2008.07.008
Fernagut, P. O., & Tison, F. (2012). Animal models of multiple system atrophy. Neuroscience, 211, 77-82. doi:10.1016/j.neuroscience.2011.09.044
Fernandez, O., Arnal-Garcia, C., Arroyo-Gonzalez, R., Brieva, L., Calles-Hernandez, M. C., Casanova-Estruch, B., . . . Post, E. G. (2013). Review of the novelties presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (III). Rev Neurol, 57(7), 317-329.
Fierabracci, A., Del Fattore, A., Luciano, R., Muraca, M., Teti, A., & Muraca, M. (2015). Recent advances in mesenchymal stem cell immunomodulation: the role of microvesicles. Cell Transplant, 24(2), 133-149. doi:10.3727/096368913X675728
Frolich, K., Hagen, R., & Kleinsasser, N. (2014). [Adipose-derived Stromal Cells (ASC) - Basics and Therapeutic Approaches in Otorhinolaryngology]. Laryngorhinootologie, 93(6), 369-380. doi:10.1055/s-0034-1367080
Gash, D. M., Zhang, Z., Ovadia, A., Cass, W. A., Yi, A., Simmerman, L., . . . Gerhardt, G. A. (1996). Functional recovery in parkinsonian monkeys treated with GDNF. Nature, 380(6571), 252-255. doi:10.1038/380252a0
Glinka, Y., Gassen, M., & Youdim, M. B. (1997). Mechanism of 6-hydroxydopamine neurotoxicity. J Neural Transm Suppl, 50, 55-66.
Gordon, G. R., Mulligan, S. J., & MacVicar, B. A. (2007). Astrocyte control of the cerebrovasculature. Glia, 55(12), 1214-1221. doi:10.1002/glia.20543
Graham, J. G., & Oppenheimer, D. R. (1969). Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy. J Neurol Neurosurg Psychiatry, 32(1), 28-34.
Guillemin, G. J. (2012). Quinolinic acid, the inescapable neurotoxin. FEBS J, 279(8), 1356-1365. doi:10.1111/j.1742-4658.2012.08485.x
Hardy, J., Lewis, P., Revesz, T., Lees, A., & Paisan-Ruiz, C. (2009). The genetics of Parkinson's syndromes: a critical review. Curr Opin Genet Dev, 19(3), 254-265. doi:10.1016/j.gde.2009.03.008
Hassan, W. U., Greiser, U., & Wang, W. (2014). Role of adipose-derived stem cells in wound healing. Wound Repair Regen, 22(3), 313-325. doi:10.1111/wrr.12173
Hidalgo-Figueroa, M., Bonilla, S., Gutierrez, F., Pascual, A., & Lopez-Barneo, J. (2012). GDNF is predominantly expressed in the PV+ neostriatal interneuronal ensemble in normal mouse and after injury of the nigrostriatal pathway. J Neurosci, 32(3), 864-872. doi:10.1523/JNEUROSCI.2693-11.2012
Hughes, A. J., Colosimo, C., Kleedorfer, B., Daniel, S. E., & Lees, A. J. (1992). The dopaminergic response in multiple system atrophy. J Neurol Neurosurg Psychiatry, 55(11), 1009-1013.
Kahle, P. J. (2008). alpha-Synucleinopathy models and human neuropathology: similarities and differences. Acta Neuropathol, 115(1), 87-95. doi:10.1007/s00401-007-0302-x
Kaindlstorfer, C., Garcia, J., Winkler, C., Wenning, G. K., Nikkhah, G., & Dobrossy, M. D. (2012). Behavioral and histological analysis of a partial double-lesion model of parkinson-variant multiple system atrophy. J Neurosci Res, 90(6), 1284-1295. doi:10.1002/jnr.23021
Kamp, F., Exner, N., Lutz, A. K., Wender, N., Hegermann, J., Brunner, B., . . . Haass, C. (2010). Inhibition of mitochondrial fusion by alpha-synuclein is rescued by PINK1, Parkin and DJ-1. EMBO J, 29(20), 3571-3589. doi:10.1038/emboj.2010.223
Kapur, S. K., & Katz, A. J. (2013). Review of the adipose derived stem cell secretome. Biochimie, 95(12), 2222-2228. doi:10.1016/j.biochi.2013.06.001
Karpinar, D. P., Balija, M. B., Kugler, S., Opazo, F., Rezaei-Ghaleh, N., Wender, N., . . . Zweckstetter, M. (2009). Pre-fibrillar alpha-synuclein variants with impaired beta-structure increase neurotoxicity in Parkinson's disease models. EMBO J, 28(20), 3256-3268. doi:10.1038/emboj.2009.257
Kaufmann, H., Freeman, R., Biaggioni, I., Low, P., Pedder, S., Hewitt, L. A., . . . Investigators, N. O. H. (2014). Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial. Neurology, 83(4), 328-335. doi:10.1212/WNL.0000000000000615
Kirik, D., Rosenblad, C., & Bjorklund, A. (1998). Characterization of behavioral and neurodegenerative changes following partial lesions of the nigrostriatal dopamine system induced by intrastriatal 6-hydroxydopamine in the rat. Exp Neurol, 152(2), 259-277. doi:10.1006/exnr.1998.6848
Kollensperger, M., Stefanova, N., Reindl, M., Poewe, W., & Wenning, G. K. (2007). Loss of dopaminergic responsiveness in a double lesion rat model of the Parkinson variant of multiple system atrophy. Mov Disord, 22(3), 353-358. doi:10.1002/mds.21251
Kumar, R., Agarwal, A. K., & Seth, P. K. (1995). Free radical-generated neurotoxicity of 6-hydroxydopamine. J Neurochem, 64(4), 1703-1707.
Lee, P. H., Lee, J. E., Kim, H. S., Song, S. K., Lee, H. S., Nam, H. S., . . . Sohn, Y. H. (2012). A randomized trial of mesenchymal stem cells in multiple system atrophy. Ann Neurol, 72(1), 32-40. doi:10.1002/ana.23612
Liqing, Y., Jia, G., Jiqing, C., Ran, G., Fei, C., Jie, K., . . . Cheng, Z. (2011). Directed differentiation of motor neuron cell-like cells from human adipose-derived stem cells in vitro. Neuroreport, 22(8), 370-373. doi:10.1097/WNR.0b013e3283469615
Low, P. A., Robertson, D., Gilman, S., Kaufmann, H., Singer, W., Biaggioni, I., . . . Galpern, W. R. (2014). Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol, 13(3), 268-275. doi:10.1016/S1474-4422(13)70301-6
Maruyama, W., Nitta, A., Shamoto-Nagai, M., Hirata, Y., Akao, Y., Yodim, M., . . . Naoi, M. (2004). N-Propargyl-1 (R)-aminoindan, rasagiline, increases glial cell line-derived neurotrophic factor (GDNF) in neuroblastoma SH-SY5Y cells through activation of NF-kappaB transcription factor. Neurochem Int, 44(6), 393-400.
Mishizen-Eberz, A. J., Norris, E. H., Giasson, B. I., Hodara, R., Ischiropoulos, H., Lee, V. M., . . . Lynch, D. R. (2005). Cleavage of alpha-synuclein by calpain: potential role in degradation of fibrillized and nitrated species of alpha-synuclein. Biochemistry, 44(21), 7818-7829. doi:10.1021/bi047846q
Monville, C., Torres, E. M., & Dunnett, S. B. (2006). Comparison of incremental and accelerating protocols of the rotarod test for the assessment of motor deficits in the 6-OHDA model. J Neurosci Methods, 158(2), 219-223. doi:10.1016/j.jneumeth.2006.06.001
Mosharov, E. V., Staal, R. G., Bove, J., Prou, D., Hananiya, A., Markov, D., . . . Sulzer, D. (2006). Alpha-synuclein overexpression increases cytosolic catecholamine concentration. J Neurosci, 26(36), 9304-9311. doi:10.1523/JNEUROSCI.0519-06.2006
Na Kim, H., Yeol Kim, D., Hee Oh, S., Sook Kim, H., Suk Kim, K., & Hyu Lee, P. (2017). Feasibility and Efficacy of Intra-Arterial Administration of Mesenchymal Stem Cells in an Animal Model of Double Toxin-Induced Multiple System Atrophy. Stem Cells Transl Med, 6(5), 1424-1433. doi:10.1002/sctm.16-0438
Nakamura, K., Nemani, V. M., Azarbal, F., Skibinski, G., Levy, J. M., Egami, K., . . . Edwards, R. H. (2011). Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein alpha-synuclein. J Biol Chem, 286(23), 20710-20726. doi:10.1074/jbc.M110.213538
Ng, T. K., Fortino, V. R., Pelaez, D., & Cheung, H. S. (2014). Progress of mesenchymal stem cell therapy for neural and retinal diseases. World J Stem Cells, 6(2), 111-119. doi:10.4252/wjsc.v6.i2.111
Papapetropoulos, S., Tuchman, A., Laufer, D., Papatsoris, A. G., Papapetropoulos, N., & Mash, D. C. (2007). Causes of death in multiple system atrophy. J Neurol Neurosurg Psychiatry, 78(3), 327-329. doi:10.1136/jnnp.2006.103929
Park, H. J., Shin, J. Y., Kim, H. N., Oh, S. H., & Lee, P. H. (2014). Neuroprotective effects of mesenchymal stem cells through autophagy modulation in a parkinsonian model. Neurobiol Aging, 35(8), 1920-1928. doi:10.1016/j.neurobiolaging.2014.01.028
Park, H. J., Shin, J. Y., Lee, B. R., Kim, H. O., & Lee, P. H. (2012). Mesenchymal stem cells augment neurogenesis in the subventricular zone and enhance differentiation of neural precursor cells into dopaminergic neurons in the substantia nigra of a parkinsonian model. Cell Transplant, 21(8), 1629-1640. doi:10.3727/096368912X640556
Pinton, P., Giorgi, C., Siviero, R., Zecchini, E., & Rizzuto, R. (2008). Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis. Oncogene, 27(50), 6407-6418. doi:10.1038/onc.2008.308
Poewe, W., Mahlknecht, P., & Krismer, F. (2015). Therapeutic advances in multiple system atrophy and progressive supranuclear palsy. Mov Disord, 30(11), 1528-1538. doi:10.1002/mds.26334
Poewe, W., Seppi, K., Fitzer-Attas, C. J., Wenning, G. K., Gilman, S., Low, P. A., . . . Rasagiline-for, M. S. A. i. (2015). Efficacy of rasagiline in patients with the parkinsonian variant of multiple system atrophy: a randomised, placebo-controlled trial. Lancet Neurol, 14(2), 145-152. doi:10.1016/S1474-4422(14)70288-1
Rice, C. M., Kemp, K., Wilkins, A., & Scolding, N. J. (2013). Cell therapy for multiple sclerosis: an evolving concept with implications for other neurodegenerative diseases. Lancet, 382(9899), 1204-1213. doi:10.1016/S0140-6736(13)61810-3
Rozas, G., & Labandeira Garcia, J. L. (1997). Drug-free evaluation of rat models of parkinsonism and nigral grafts using a new automated rotarod test. Brain Res, 749(2), 188-199. doi:10.1016/S0006-8993(96)01162-6
Ruetze, M., & Richter, W. (2014). Adipose-derived stromal cells for osteoarticular repair: trophic function versus stem cell activity. Expert Rev Mol Med, 16, e9. doi:10.1017/erm.2014.9
Scholz, S. W., Houlden, H., Schulte, C., Sharma, M., Li, A., Berg, D., . . . Gasser, T. (2009). SNCA variants are associated with increased risk for multiple system atrophy. Ann Neurol, 65(5), 610-614. doi:10.1002/ana.21685
Senarath-Yapa, K., McArdle, A., Renda, A., Longaker, M. T., & Quarto, N. (2014). Adipose-derived stem cells: a review of signaling networks governing cell fate and regenerative potential in the context of craniofacial and long bone skeletal repair. Int J Mol Sci, 15(6), 9314-9330. doi:10.3390/ijms15069314
Solano, S. M., Miller, D. W., Augood, S. J., Young, A. B., & Penney, J. B., Jr. (2000). Expression of alpha-synuclein, parkin, and ubiquitin carboxy-terminal hydrolase L1 mRNA in human brain: genes associated with familial Parkinson's disease. Ann Neurol, 47(2), 201-210.
Stagg, J. (2007). Immune regulation by mesenchymal stem cells: two sides to the coin. Tissue Antigens, 69(1), 1-9. doi:10.1111/j.1399-0039.2006.00739.x
Stefanova, N., Tison, F., Reindl, M., Poewe, W., & Wenning, G. K. (2005). Animal models of multiple system atrophy. Trends Neurosci, 28(9), 501-506. doi:10.1016/j.tins.2005.07.002
Stefanova, N., & Wenning, G. K. (2015). Animal models of multiple system atrophy. Clin Auton Res, 25(1), 9-17. doi:10.1007/s10286-014-0266-6
Sun, H., Hou, Z., Yang, H., Meng, M., Li, P., Zou, Q., . . . Xiao, Z. (2014). Multiple systemic transplantations of human amniotic mesenchymal stem cells exert therapeutic effects in an ALS mouse model. Cell Tissue Res, 357(3), 571-582. doi:10.1007/s00441-014-1903-z
Tomac, A., Lindqvist, E., Lin, L. F., Ogren, S. O., Young, D., Hoffer, B. J., & Olson, L. (1995). Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature, 373(6512), 335-339. doi:10.1038/373335a0
Tomac, A., Widenfalk, J., Lin, L. F., Kohno, T., Ebendal, T., Hoffer, B. J., & Olson, L. (1995). Retrograde axonal transport of glial cell line-derived neurotrophic factor in the adult nigrostriatal system suggests a trophic role in the adult. Proc Natl Acad Sci U S A, 92(18), 8274-8278.
Ubhi, K., Rockenstein, E., Mante, M., Inglis, C., Adame, A., Patrick, C., . . . Masliah, E. (2010). Neurodegeneration in a transgenic mouse model of multiple system atrophy is associated with altered expression of oligodendroglial-derived neurotrophic factors. J Neurosci, 30(18), 6236-6246. doi:10.1523/JNEUROSCI.0567-10.2010
Vekrellis, K., Rideout, H. J., & Stefanis, L. (2004). Neurobiology of alpha-synuclein. Mol Neurobiol, 30(1), 1-21. doi:10.1385/MN:30:1:001
Vogiatzi, T., Xilouri, M., Vekrellis, K., & Stefanis, L. (2008). Wild type alpha-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J Biol Chem, 283(35), 23542-23556. doi:10.1074/jbc.M801992200
Wagers, A. J., & Weissman, I. L. (2004). Plasticity of adult stem cells. Cell, 116(5), 639-648.
Watanabe, H., Saito, Y., Terao, S., Ando, T., Kachi, T., Mukai, E., . . . Sobue, G. (2002). Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients. Brain, 125(Pt 5), 1070-1083.
Weinreb, O., Amit, T., Bar-Am, O., & Youdim, M. B. (2007). Induction of neurotrophic factors GDNF and BDNF associated with the mechanism of neurorescue action of rasagiline and ladostigil: new insights and implications for therapy. Ann N Y Acad Sci, 1122, 155-168. doi:10.1196/annals.1403.011
Yager, L. M., Garcia, A. F., Wunsch, A. M., & Ferguson, S. M. (2015). The ins and outs of the striatum: role in drug addiction. Neuroscience, 301, 529-541. doi:10.1016/j.neuroscience.2015.06.033
Yoon, H. H., Kim, Y. H., Shin, E. S., & Jeon, S. R. (2014). A rat model of striatonigral degeneration generated by simultaneous injection of 6-hydroxydopamine into the medial forebrain bundle and quinolinic acid into the striatum. J Korean Med Sci, 29(11), 1555-1561. doi:10.3346/jkms.2014.29.11.1555
連結至畢業學校之論文網頁點我開啟連結
註: 此連結為研究生畢業學校所提供,不一定有電子全文可供下載,若連結有誤,請點選上方之〝勘誤回報〞功能,我們會盡快修正,謝謝!
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top