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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77997完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 余佳慧(Linda Chia-Hui Yu) | |
| dc.contributor.author | Yi-Ting Yang | en |
| dc.contributor.author | 楊依婷 | zh_TW |
| dc.date.accessioned | 2021-07-11T14:39:15Z | - |
| dc.date.available | 2025-08-16 | |
| dc.date.copyright | 2020-09-10 | |
| dc.date.issued | 2020 | |
| dc.date.submitted | 2020-08-17 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77997 | - |
| dc.description.abstract | 背景: 腸躁症 (Irritable bowel syndrome, IBS) 為伴隨反覆性腹痛之功能性腸胃道疾病。腸躁症的危險因子包含遺傳因素、精神壓力、腸道慢性發炎、腸道感染病史等。過去研究發現腸躁症患者結直腸黏膜層檢體中高密度的神經纖維分布及較高表現量的神經營養因子，如:神經生長因子 (Nerve Growth Factor, NGF) 及腦源性神經營養因子 (Brain-derived neurotrophic factor, BDNF)，與腸躁症患者腹痛程度有關。此外，神經內分泌物質的失調，如血清素 (Serotonin, 5-HT) 與膽囊收縮素 (cholecystokinin, CCK)，也被指出參與在腸道痛覺機制中。本篇研究目的為探討血清素受器在神經纖維延長機制中扮演之角色，以及神經內分泌物質與神經營養因子間之交互作用。 材料與方法: 兩種類腸躁症動物模式包含使用2,4,6-三硝基苯磺酸誘發的後腸炎性類腸躁症之PT小鼠，以及寄生蟲後排除期/慢性避水壓力試驗之GW/WAS小鼠。藉由結直腸撐張刺激所引發的內臟動器反應來測定其腹痛程度，並以腹腔注射方式給予PT小鼠第七型血清素受器化合物CYY073-b，測試其對PT小鼠腸道疼痛感覺之效用。另外也收集動物大腸黏膜、腸段全組織以及背根神經節 (胸椎第九節至腰椎第一節以及腰椎第五節至薦椎第一節) 作核醣核酸分析。神經纖維長度、mRNA及蛋白表現量則是在SH-SY5Y人類神經細胞株 (human neuroblastoma) 中探討，以無菌小鼠腸道組織上清液或外加血清素及神經營養因子NGF、BDNF，觀察神經纖維延長及細胞中與神經內分泌物質及神經營養因子相關之基因和蛋白表現量。 結果: 在兩種類腸躁症動物模式皆發現有內臟高敏感性的現象，給予PT小鼠第七型血清素受器化合物CYY073-b可抑制其腸道疼痛感覺。PT小鼠的大腸全組織中，tryptophan hydroxylase 2 (TPH2)、5-HT7R、BDNF基因表現量上升，而TPH1、NGF基因表現量無改變；PT小鼠的大腸黏膜和背根神經節中，這些基因皆無改變。GW小鼠的大腸全組織中，p75 neurotrophin receptor (p75NTR) and Tropomyosin-related kinase receptor B (TrkB)基因表現量上升，而其餘基因有上升趨勢但無統計差異。在SH-SY5Y人類神經細胞株的實驗方面，以無菌之小鼠腸道組織上清液刺激會使神經細胞的神經內分泌物質及神經營養因子相關之基因表現量上升，但PT組與Sham組小鼠之間並無差異。在神經細胞實驗中，外加血清素使其神經纖維延長之效果可受5-HT7R拮抗劑抑制。以血清素或第七型血清素受器促進劑LP-211刺激之神經細胞，其NGF、BDNF及其受器p75NTR、TrkB 和CCK及其受器CCK-AR、CCK-BR mRNA 表現量上升，且此現象可受5-HT7R拮抗劑抑制。以NGF或BDNF刺激之神經細胞，其TPH2、5-HT7R mRNA表現量增加，而TPH1、CCK及其受器CCK-AR、CCK-BR mRNA表現量則無顯著差異。 結論: 本篇研究證實，類腸躁症動物模式小鼠之腸道痛覺異常可受第七型血清素受器拮抗劑所抑制。而神經內分泌物質與神經營養因子間存在交互作用，血清素透過第七型血清素受器與神經營養因子形成之正回饋反應可促進神經纖維延長。 | zh_TW |
| dc.description.abstract | Background: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder with recurrent abdominal pain. Risk factors related to IBS include hereditary factors, psychological stress, chronic inflammation, and history of intestinal infection etc. Higher nerve fiber density and neurotrophin levels such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were found in colorectal biopsies associated with pain scores in IBS patients. In addition, dysregulation of neuroendocrines such 5-hydroxytryptamine (5-HT) and cholecystokinin (CCK) was involved in intestinal pain. Our aim is to investigate the interaction between neurotrophins and neuroendocrines in the mechanisms of intestinal neurite outgrowth and visceral hypersensitivity. Materials and Methods: Two animal models were used, including mice post-inflammatory of Trinitrobenzene sulfonic acid-induced colitis (PT) and mice that received post-giardiasis and chronic water avoidance stress (GW/WAS). Visceromotor response (VMR) to colorectal distension was measured to quantify intestinal pain. PT mice were used to test the effect of newly synthesized 5-HT7 receptor (5-HT7R) ligand―CYY073-b on visceral hypersensitivity. Colonic mucosa, colonic whole tissue, and Thoracic vertebra 9 to Lumbar vertebra 1 and Lumbar vertebra 5 to Sacral vertebra 1 (T9 - L1 and L5-S1) of dorsal root ganglia (DRG) collected from animals are used for measurement of mRNA expression. The human neuroblastoma SH-SY5Y cells were used for analysis of nerve fiber length, real-time PCR and Western blotting. Results: Higher VMR was found in the two animal models, and the visceral hypersensitivity in PT mice was inhibited by the newly synthesized 5-HT7R ligand―CYY073-b. Higher tryptophan hydroxylase 2 (TPH2), 5-HT7R, and BDNF mRNA expression were found in the colonic whole tissues of PT mice, whereas no change was seen in the TPH1 and NGF levels; no difference of these gene transcription was observed in mucosal tissues and DRG samples between PT and Sham mice. Higher levels of p75 neurotrophin receptor (p75NTR) and Tropomyosin-related kinase receptor B (TrkB) were found in the colonic whole tissues of GW mice but only increased trend was seen in other molecules without statistical significance. For the experiments in differentiated SH-SY5Y neural cells, all neuroendocrine- and neurotrophin-related gene expression were increased following incubation with bacteria-free mouse colonic supernatant; however, no difference was seen between PT and sham groups of colonic supernatants. In the differentiated SH-SY5Y neural cells, neurite outgrowth that are induced by 5-HT were inhibited by 5-HT7R antagonists. Treatment with 5-HT and 5-HT7R agonist LP-211 increased the NGF, BDNF, p75NTR, TrkB, CCK and CCK receptor mRNA expression, but not TrkA level, in neural cells. Treatment with recombinant NGF and BDNF increased the TPH2 and 5-HT7R mRNA expression, but not TPH1, CCK or CCK receptor levels. Conclusion: Colonic hyperalgesia of IBS-like animal model was inhibited by 5-HT7R antagonists. A positive feedback loop was observed between neuroendocrine and neurotrophin expression. Serotonin contributed to neurite outgrowth by promoting neurotrophin expression via 5-HT7R. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T14:39:15Z (GMT). No. of bitstreams: 1 U0001-1508202023214400.pdf: 2459935 bytes, checksum: 6e6e99a56beb60cf2d5ede367984f79c (MD5) Previous issue date: 2020 | en |
| dc.description.tableofcontents | 壹、前言 1 1. 神經系統對腸道功能之調控 1 2. 雙向腦腸軸 (bidirectional brain-gut axis) 2 3. 內臟痛覺傳遞途徑 2 3.1上行痛覺傳遞 (Ascending visceral pain pathway) 2 3.2 下行痛覺傳遞 (Descending visceral pain pathway) 3 3.3 內臟高敏感性 (visceral hypersensitivity) 3 4. 腸躁症 (Irritable bowel syndrome, IBS) 3 4.1 流行病學 3 4.2 診斷標準及亞型分類 4 4.3 危險因子 4 4.3.1精神壓力 5 4.3.2腸胃道感染 5 4.3.3慢性腸道發炎 6 4.4類腸躁症動物模式 6 4.4.1避水行為誘發精神壓力模式 7 4.4.2梨形鞭毛蟲感染排除後模式 7 4.4.3三硝基苯黃酸誘導發炎復原模式 8 5. 內臟高敏感性 (visceral hypersensitivity) 之相關分子機制 9 5.1離子通道及痛覺受器表現量改變 9 5.2 神經纖維數目及結構改變 10 5.3 神經內分泌物質及其受器表現量改變 10 5.3.1 血清素產量或代謝異常 11 5.3.2血清素受器表現量異常 13 5.3.3 膽囊收縮素及其受器表現量異常 14 5.4 神經營養因子及其受器表現量改變 15 6. 研究目的 16 貳、材料與方法 17 1. 實驗動物 17 2. 後腸炎性類腸躁症模式 17 2.1 三硝基苯磺酸 (2,4,6-trinitrobenzenesulfonic acid solution, TNBS) 誘導小鼠結腸炎模式 17 2.2新合成血清素受器化合物 18 2.2.1藥物試驗流程 19 3. 後感染與精神壓力類腸躁症模式 20 4. 結直腸撐張刺激-內臟動器反應分析 (Colorectal distension-Visceromotor response, CRD-VMR) 21 4.1 腹外斜肌電極埋入手術 21 4.2 結直腸撐張刺激-內臟動器反應實驗 22 5. 動物檢體收集 23 6. 細胞實驗 24 6.1 SH-SY5Y細胞株 24 6.2 實驗所需細胞種植濃度 24 6.3 外加刺激物實驗 25 6.3.1 測試胎牛血清濃度之影響 25 6.3.2 腸道組織上清液刺激 25 6.3.2.1 腸組織無菌上清液 (bacteria-free gut supernatant) 製備 25 6.3.2.2 腸道組織上清液刺激實驗 26 6.3.3 神經營養因子刺激 27 6.3.4血清素刺激與抑制劑及促進劑實驗 27 6.3.4.1血清素刺激 27 6.3.4.2血清素的刺激下抑制劑及促進劑預處理實驗 27 6.3.5第七型血清素受器促進劑 (5-HT7 receptor agonist) 刺激 28 6.4 神經纖維生長 (neurite outgrowth) 實驗 29 6.4.1 細胞影像攝影與神經細胞纖維長度測量 29 7. 核糖核酸 (mRNA) 測定 30 7.1核糖核酸之萃取 30 7.1.1萃取組織核糖核酸 30 7.1.2萃取細胞核糖核酸 30 7.2反轉錄聚合酶連鎖反應 (Reverse Transcription Polymerase Chain Reaction, RT-PCR) 31 7.3即時聚合酶連鎖反應 (Real time polymerase chain reaction, real-time PCR) 31 8. 西方墨點法 (Western blotting) 36 8.1 第七型血清素受器促進劑刺激與神經營養因子刺激實驗 36 8.1.1第七型血清素受器促進劑刺激 36 8.1.2神經營養因子刺激 36 8.2 SH-SY5Y細胞蛋白質萃取 37 8.3 蛋白質電泳 (SDS-PAGE) 37 8.4 蛋白質分析 37 9. 統計方法 38 參、實驗結果 39 1. 類腸躁症小鼠模式之腸道痛覺測定 39 1.1 對照組 (Sham) 及後腸炎性類腸躁症模式 (Post-TNBS, PT) 小鼠的內臟動器反應: 腹腔注射給予單一劑量第七型血清素受器配體之影響 39 1.2 精神壓力誘發之類腸躁症模式 (water avoidance stress, WAS) 小鼠的內臟動器反應 39 2. 類腸躁症小鼠模式之神經內分泌物質與神經營養因子相關基因表現 39 2.1 PT小鼠之神經內分泌物質與神經營養因子相關基因表現 39 2.1.1大腸黏膜層中神經內分泌物質、神經營養因子及其受器基因表現 40 2.1.2大腸腸段全組織中神經內分泌物質、神經營養因子及其受器基因表現 40 2.1.3背根神經節中神經內分泌物質、神經營養因子及其受器基因表現 41 3.1 GW小鼠之神經內分泌物質與神經營養因子相關基因表現 41 3.1.1 大腸腸段全組織中神經內分泌物質、神經營養因子及其受器基因表現 41 4.1 WAS小鼠之神經內分泌物質與神經營養因子相關基因表現 41 4.1.1 大腸腸段全組織中神經內分泌物質、神經營養因子及其受器基因表現 41 3. 利用人類SH-SY5Y神經細胞探討神經內分泌物質與神經營養因子間之交互作用 42 3.1 小鼠腸道上清液對SH-SY5Y神經細胞神經內分泌物質與神經營養因子及其受器基因表現量之影響 42 3.2 探討血清素受器亞型在SH-SY5Y神經細胞纖維延長機制中扮演之角色 43 3.3 探討外加神經內分泌物質或神經營養因子對SH-SY5Y神經細胞及特定基因表現量之影響 43 3.3.1 外加血清素對SH-SY5Y神經細胞神經營養因子及其受器基因表現量之影響 43 3.3.2 外加第七型血清素受器促進劑對SH-SY5Y神經細胞神經營養因子及其受器基因表現量之影響 43 3.3.3預處理抑制劑及促進劑對血清素刺激SH-SY5Y神經細胞造成神經營養因子及其受器基因表現量之影響 44 3.3.4 外加神經營養因子對SH-SY5Y神經細胞血清素合成酵素及血清素受器基因表現量之影響 45 3.3.5 探討血清素及神經營養因子對SH-SY5Y神經細胞膽囊收縮素及其受器基因表現量之影響 45 3.3.5.1 外加血清素對SH-SY5Y神經細胞的膽囊收縮素及其受器基因表現量之影響 45 3.3.5.2 探討第七型血清素受器在血清素促進SH-SY5Y神經細胞膽囊收縮素及其受器基因表現量影響中之角色 46 3.3.5.3 外加神經營養因子對SH-SY5Y神經細胞膽囊收縮素及其受器基因表現量之影響 46 3.4 探討細胞培養液的胎牛血清 (fetal bovine serum, FBS) 對SH-SY5Y神經細胞特定基因之影響 47 3.5 探討外加第七型血清素受器促進劑或神經營養因子對SH-SY5Y神經細胞特定蛋白表現量之影響 48 肆、討論 49 伍、附圖 55 陸、參考文獻 92 | |
| dc.language.iso | zh-TW | |
| dc.subject | 神經內分泌物質 | zh_TW |
| dc.subject | 內臟高敏感性 | zh_TW |
| dc.subject | 腸躁症 | zh_TW |
| dc.subject | 神經纖維延長 | zh_TW |
| dc.subject | 血清素受器 | zh_TW |
| dc.subject | 神經營養因子 | zh_TW |
| dc.subject | Irritable bowel syndrome | en |
| dc.subject | visceral hypersensitivity | en |
| dc.subject | neuroendocrine | en |
| dc.subject | neurotrophin | en |
| dc.subject | neurite outgrowth | en |
| dc.subject | 5-HT receptors | en |
| dc.title | 內臟高敏感性機制中神經營養因子與神經內分泌之交互作用 | zh_TW |
| dc.title | Interaction Between Neurotrophins and Neuroendocrines in Visceral Hypersensitivity | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 108-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 吳明賢(Ming-Shiang Wu),忻凌偉(Ling-Wei Hsin),張哲逢(Che-Feng Chang) | |
| dc.subject.keyword | 腸躁症,內臟高敏感性,神經內分泌物質,神經營養因子,神經纖維延長,血清素受器, | zh_TW |
| dc.subject.keyword | Irritable bowel syndrome,visceral hypersensitivity,neuroendocrine,neurotrophin,neurite outgrowth,5-HT receptors, | en |
| dc.relation.page | 103 | |
| dc.identifier.doi | 10.6342/NTU202003542 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2020-08-17 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生理學研究所 | zh_TW |
| dc.date.embargo-lift | 2025-08-16 | - |
| 顯示於系所單位： | 生理學科所 | |
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