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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 余佳慧 | zh_TW |
dc.contributor.advisor | en | |
dc.contributor.author | 林俐妤 | zh_TW |
dc.contributor.author | Li-Yu Lin | en |
dc.date.accessioned | 2021-07-10T22:07:40Z | - |
dc.date.available | 2024-02-28 | - |
dc.date.copyright | 2018-10-11 | - |
dc.date.issued | 2018 | - |
dc.date.submitted | 2002-01-01 | - |
dc.identifier.citation | 1. Greenwood-Van Meerveld, B., A.C. Johnson, and D. Grundy, Gastrointestinal Physiology and Function. Handb Exp Pharmacol, 2017. 239: p. 1-16.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77539 | - |
dc.description.abstract | 腸躁症(Irritable Bowel Syndrome, IBS)是一種功能性腸胃道疾病,患者有長期的反覆性腹痛、及排便型態的改變,但在內視鏡及糞便的篩檢卻沒有出現腸胃道結構上的損害及病原體的存在。腸躁症的危險因子包含遺傳因子、心理壓力、慢性發炎及腸道感染病史等。治療方面,2015年美國食品藥品管理局(FDA)核准Rifaximin (RFX)用於治療腸躁症腹瀉型患者,但機轉尚未明確。另外先前研究發現,腸躁症患者結直腸黏膜層檢體中的神經纖維密度高。因此我的研究目的是利用兩種腸躁症動物模式去探討RFX對於腸道痛覺反應及神經可塑性的影響。實驗包含兩種類腸躁症動物模式,第一種是結合雙重誘導因子,包括寄生蟲感染(Giardia)以及避水壓力試驗(WAS),此組稱為GW小鼠;另一種則是使用2, 4, 6-三硝基苯磺酸誘導成腸炎,此組稱為TNBS小鼠。經口給予RFX及LWX(血清素受器配體)後,在GW及TNBS小鼠模式進行結直腸撐張刺激測定內臟敏感性,並進行腸道組織神經標定物PGP9.5及血清素受器的螢光免疫染色。利用腸道組織製成上清液並添加至人類神經瘤SH-SY5Y細胞中,以探討不同動物處理組對於神經纖維延長的調控。最後,收集腸躁症患者及健康者的結腸黏膜檢體測定神經纖維分布。GW及TNBS小鼠經口給予RFX、LWX及RFX+LWX後,均有顯著下降內臟高敏感性反應,但腸道蠕動性並無差異。利用螢光免疫染色技術發現GW及TNBS小鼠結腸黏膜組織之PGP9.5表現較正常組別量高,而腸躁症患者降結腸檢體中之PGP9.5表現比起健康者分布量亦較高。GW小鼠經口給予RFX或LWX組別之結腸黏膜組織PGP9.5表現量均有顯著降低。GW及TNBS小鼠給予RFX後,腸道黏膜層的血清素受器mRNA和蛋白質表現量均無顯著差異。此外,將GW及TNBS小鼠腸道組織上清液或5-HT添加至人類神經瘤SH-SY5Y細胞後,會引起神經纖維延長,而GW+RFX或TNBS+RFX小鼠上清液組別則無法引起纖維延長。本篇實驗證實,RFX單一給予或與新合成之血清素受器配體合併使用皆可透過抑制神經纖維延長來降低內臟高敏感性的反應。在類腸躁症動物模式及腸躁症患者結腸檢體中觀察到黏膜神經纖維延長,且神經纖維的延長可能由血清素調控。 | zh_TW |
dc.description.abstract | Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder with recurrent abdominal pain associated with bowel habit changes, but neither apparent structural lesion nor presence of pathogen could be found. Risk factors include hereditary factor, psychological stress, chronic inflammation and history of infection etc. Rifaximin (RFX) was approved by FDA in USA in 2015 for the treatment of IBS with diarrhea; however, the mechanism is not clear. Previous study documented high density of neurites in colon mucosa of IBS patients. Our aim is to investigate the effect of RFX on intestinal nociception and neuroplastisity in IBS-like mouse models. Two mouse models were used, including post-giardiasis with water avoidance stress (GW) and post resolution of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Mice were given RFX or LWX (a 5-HT receptor ligand) and tested for colorectal distension-visceromotor response (CRD-VMR). Immunofluorescence (IF) staining of PGP9.5 (a pan-neuron marker) and 5-HT receptors were conducted. Mouse colonic supernatant was added to human neuroblastoma SH-SY5Y cells to evaluate nerve fiber outgrowth. Lastly, colonic biopsies of IBS patients and healthy controls were collected to examine mucosal nerve distribution. Decrease in visceral hypersensitivity was observed in the GW and TNBS mice given RFX, LWX, or RFX+LWX; however, no difference in intestinal transit was found. By immunofluorescence staining, higher PGP9.5 immunoreactivity was found in the colonic mucosa of GW and TNBS mice compared to control mice, and those in IBS patients were higher than healthy controls. Moreover, the PGP9.5 fluorescent intensity was lower in the colonic mucosa of GW+RFX and GW+LWX mice compared to GW-veh mice. After given RFX, the mRNA and protein levels of 5-HT receptors in the mucosal layers were similar among mouse groups. Lastly, GW and TNBS mouse colonic supernatant or exogenous 5-HT induced nerve fiber outgrowth in SH-SY5Y cells, whereas the nerve fiber length was reduced in cells incubated with RFX-treated GW and TNBS mouse supernatant. RFX alone or in combination with LWX decreased visceral hypersensitivity partly via inhibition of mucosal neurite outgrowth in IBS-like mouse models. Extension of nerve fiber length in the mucosa was found in IBS-like mice and IBS patients, which may be mediated by 5-HT. | en |
dc.description.provenance | Made available in DSpace on 2021-07-10T22:07:40Z (GMT). No. of bitstreams: 1 ntu-107-R05441007-1.pdf: 3934415 bytes, checksum: ab2f47f23b9cd76b3b6bc4ef2a76bbe0 (MD5) Previous issue date: 2018 | en |
dc.description.tableofcontents | 致謝 I
摘要 II Abstract IV 目錄 VI 圖目錄 IX 壹、 前言 1 1. 腸道結構及生理功能 1 1.1腸道感覺傳入神經元(afferent neurons)的分布 1 1.2傳入神經之物理及化學性調控 2 1.3傳入神經所釋放的神經傳導物質 2 1.4釋放血清素的腸道神經內分泌細胞 2 1.5血清素受體和功能 3 2. 腦腸雙向軸(bidirectional brain-gut axis) 4 3. 內臟痛覺傳遞途徑 5 3.1上行痛覺傳遞(Ascending visceral pain pathway) 5 3.2下行痛覺傳遞(Descending visceral pain pathway) 6 3.3內臟高敏感性(Visceral hypersensitivity) 6 4. 腸躁症(Irritable bowel syndrome, IBS) 7 4.1流行病學 7 4.2臨床研究 8 4.3風險因子 8 4.4類腸躁症動物模式 11 5. 腸躁症內臟高敏感性相關可能機轉 14 5.1神經細胞膜上痛覺受器表現量改變 15 5.2神經纖維數目和結構改變 15 5.3神經生長因子表現量改變 16 5.4血清素及其受體表現異常 16 6. 腸躁症藥物治療 18 6.1腸躁症過去的臨床用藥 18 6.2腸躁症的最新臨床用藥 18 6.3新合成血清素受器化合物-第七型受器配體(5-HT7 receptor ligands) 19 7. 研究目的 19 貳、 材料與方法 20 1. 實驗動物 20 2. 寄生蟲感染動物模式 20 2.1實驗寄生蟲培養 20 2.2實驗寄生蟲感染方式 21 2.3寄生蟲滋養體計數 21 3. 精神壓力模式 21 4. 結腸炎模式 22 5. 新合成血清素受器化合物: 第七型受器配體(5-HT7 receptor ligands) 22 6. 抗生素類:Rifaximin和Neomycin 22 7. 實驗動物分組與流程 23 7.1梨形鞭毛蟲感染與避水壓力模式 (Giardia-Water avoidance stress, GW) 23 7.2三硝基苯磺酸誘導小鼠結腸炎模式 (2,4,6-trinitrobenzenesulfonic acid, TNBS) 24 8. 藥物試驗流程 25 8.1 RFX單獨給予 25 8.2 LWX單獨給予 26 8.3雙重藥物給予(RFX+LWX) 26 9. 結直腸撐張刺激-內臟動器反應分析(Colorectal distension-Visceromotor response, CRD-VMR) 28 10. 腸道蠕動性測試之活性碳試驗(charcoal meal test) 29 11. 腸道蠕動性測試之糞便排出量計數(fecal pellet output) 30 12. 組織切片與染色 30 12.1冷凍包埋檢體製備 30 12.2免疫螢光染色(Immunofluorescence, IF) 30 13. 細胞實驗 31 13.1使用細胞株 31 13.2神經纖維生長(neurite outgrowth)實驗 32 13.3腸組織無菌上清液(bacteria-free gut supernatant)製備 33 13.4細胞影像攝影與神經細胞纖維長度測量 34 14. 人體大腸黏膜檢體收集 34 15. 核糖核酸(mRNA)測定 35 15.1組織核糖核酸萃取 35 15.2反轉錄聚合酶連鎖反應 (Reverse Transcription Polymerase Chain Reaction, RT-PCR) 36 15.3 核糖核酸電泳分析 38 16. 西方墨點法(Western blotting) 38 16.1動物組織蛋白萃取 38 16.2蛋白質電泳(SDS-PAGE) 38 16.3蛋白質分析 39 17. 統計方法 40 18. 抗體列表 40 參、 實驗結果 41 一、 梨形鞭毛蟲後感染與避水壓力小鼠模式 41 1. 藥物給予對於Giardia-WAS誘導類腸躁症小鼠內臟高敏感性的影響 41 2. 藥物給予對於GW小鼠體重變化及腸道蠕動性的影響 41 3. GW小鼠及各處理組腸道組織中神經與血清素受體分布的情形 42 4. GW小鼠及各處理組腸道黏膜層中血清素受體第三和第四亞型的mRNA和蛋白質表現量 43 二、 三硝基苯磺酸誘導結腸炎小鼠模式 43 1. 藥物給予對於TNBS誘導類腸躁症小鼠內臟高敏感性的影響 43 2. 藥物給予對於TNBS小鼠體重變化及腸道蠕動性的影響 44 3. TNBS小鼠及各處理組腸道組織中神經與血清素受體分布的情形 44 4. TNBS小鼠及各處理組腸道黏膜層中血清素受體第三和第四亞型的mRNA和蛋白質表現量 45 三、 腸躁症患者的大腸黏膜層中血清素受器及神經分布與表現情形 46 1. 腸躁症患者與健康者腸道組織中神經(PGP9.5)分布的情形 46 2. 腸躁症患者與健康者血清素第七型血清素受體(5-HT7R)在大腸黏膜層的分布及表現量 46 3. 腸躁症患者與健康者血清素第三型及第四型血清素受體(5-HT3R、5-HT4R)在大腸黏膜層的分布及表現量 46 四、 利用SH-SY5Y神經細胞探討神經纖維變化 47 1. GW及TNBS小鼠大腸組織上清液刺激SH-SY5Y細胞造成纖維延長 47 2. 外加血清素對於SH-SY5Y神經細胞纖維延長的影響 47 3. LP-211 (5-HT7R促進劑) 對於SH-SY5Y神經細胞纖維延長的影響 48 肆、 討論 49 伍、 參考文獻 80 | - |
dc.language.iso | zh_TW | - |
dc.title | 腸躁症小鼠模式中rifaximin對於腸道痛覺反應與神經可塑性的影響 | zh_TW |
dc.title | Effect of rifaximin on intestinal nociception and neuroplasticity in mouse models of irritable bowel syndrome | en |
dc.type | Thesis | - |
dc.date.schoolyear | 106-2 | - |
dc.description.degree | 碩士 | - |
dc.contributor.oralexamcommittee | 孫錦虹;忻凌偉;吳明賢 | zh_TW |
dc.contributor.oralexamcommittee | ;; | en |
dc.subject.keyword | 腸躁症,壓力,梨形鞭毛蟲,腸炎,內臟高敏感性,利福昔明,血清素, | zh_TW |
dc.subject.keyword | Irritable bowel syndrome,stress,Giardia lamblia,colitis,visceral hypersensitivity,rifaximin,serotonin., | en |
dc.relation.page | 92 | - |
dc.identifier.doi | 10.6342/NTU201802879 | - |
dc.rights.note | 未授權 | - |
dc.date.accepted | 2018-08-13 | - |
dc.contributor.author-college | 醫學院 | - |
dc.contributor.author-dept | 生理學研究所 | - |
顯示於系所單位: | 生理學科所 |
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