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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 余佳慧 | |
| dc.contributor.author | Yu-Ting Hsieh | en |
| dc.contributor.author | 謝毓庭 | zh_TW |
| dc.date.accessioned | 2021-07-11T15:11:55Z | - |
| dc.date.available | 2029-12-31 | |
| dc.date.copyright | 2019-08-28 | |
| dc.date.issued | 2019 | |
| dc.date.submitted | 2019-08-05 | |
| dc.identifier.citation | 1. Gershon, M.D., The enteric nervous system: a second brain. Hosp Pract (1995), 1999. 34(7): p. 31-32, 35-8, 41-2 passim.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78682 | - |
| dc.description.abstract | 背景：腸躁症(Irritable Bowel Syndrome, IBS)為功能性腸胃道疾病，亦即腸道無明顯的結構或生化異常，而患者卻出現慢性且反覆性的腹痛，以及排便型態改變的臨床症狀。腸躁症的危險因子包含精神壓力、腸道慢性發炎、腸道感染病史等。然而，多因素的腸躁症疾病其潛在的病生理機制並不清楚，其中在神經-內分泌網絡機制指出，內臟高敏感性與神經內分泌物質的作用有關，如血清素(Serotonin, 5-HT)、神經生長因子(Nerve Growth Factor, NGF)和腦源性神經營養因子(Brain-Derived Neurotrophic Factor, BDNF)。過去文獻指出腸躁症患者結直腸黏膜層檢體中NGF和BDNF表現量高，且有高密度的神經纖維分布，與腹痛程度有正相關性。本篇研究目的為利用化學性誘導結腸炎復原之類腸躁症動物模式探討血清素受器對於腸道痛覺的影響，以及利用人類神經細胞模式探討血清素與神經營養因子共同調控腸道神經纖維延長的機制。
方法：實驗室先前建立兩種類腸躁症動物模式，第一種是結合雙重誘導因子即感染後排除合併避水壓力試驗，稱為GW小鼠；第二種則是使用2, 4, 6-三硝基苯磺酸誘發結腸炎復原後，此組為後腸炎性類腸躁症模式，稱為PT小鼠。經口或腹腔注射給予小鼠血清素受器化合物，進行結直腸撐張刺激所引發的內臟動器反應，測定其疼痛程度，並在結束後給予活性碳試驗，評估腸道蠕動性。在小鼠組織中使用神經標誌 PGP9.5以及血清素受器進行免疫螢光染色。利用SH-SY5Y人類神經細胞株(human neuroblastoma)來探討血清素受器在神經纖維延長的效果與機制，將GW及PT小鼠的腸道組織製成無菌上清液或外加血清素及神經營養因子刺激SH-SY5Y神經細胞，觀察神經纖維延長和細胞中特定基因的表現量。最後，由大腸鏡切片取得腸躁症患者及健康者的結腸黏膜檢體，使用免疫螢光染色觀察神經纖維及血清素受器分布位置及表現。 結果：在正常Ctrl組小鼠中，經口給予特定的血清素受器配體(CYY1005)，發現其不會影響生理疼痛感覺；而在PT組小鼠中，則可以有效降低其內臟敏感性。此外，腹腔注射新合成之血清素受器化合物(CYY073、CYY1280-3、CYY1294)於PT組小鼠，只有CYY1280-3在高撐張刺激下能顯著性降低內臟高敏感性反應，且腸道蠕動性也有顯著降低。在免疫螢光染色結果發現GW及PT小鼠結腸黏膜組織之PGP9.5與血清素受器表現量較正常組高，而腸躁症患者降結腸檢體中之PGP9.5與血清素受器表現量比起健康者分布量亦較高。利用類腸躁症動物腸道組織上清液或外加血清素及神經營養因子刺激SH-SY5Y神經細胞後，能使神經細胞纖維延長，而若先給予血清素受器配體(CYY1005)或5-HT7R拮抗劑(SB7)預先處理，則出現抑制神經纖維的延長的效果。同時，以NGF或BDNF刺激SH-SY5Y神經細胞，會促使神經營養因子受器及血清素受器表現量增加。 結論：本篇實驗證實，血清素受器有參與類腸躁症動物模式小鼠中內臟高敏感性的反應。此外，血清素與神經營養因子共同調控神經纖維延長。 | zh_TW |
| dc.description.abstract | Background：Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder, that meaning that there is no obvious structural or biochemical abnormality in the intestine. IBS patient have clinical symptoms of chronic and recurrent abdominal pain associated with bowel habit changes. Risk factors include psychological stress, chronic intestinal inflammation and history of intestinal infection etc. However, the underlying pathophysiological mechanism of multifactorial intestinal disease is unclear. In the neuro-endocrine network, visceral hypersensitivity is related to the action of neuroendocrine substances such as serotonin, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Previous study showed increased NGF and BDNF levels and high density of nerve fiber distribution in colon mucosa of IBS patients, which were correlated to abdominal pain score. Our aim is to investigate the effects of serotonin receptor on intestinal pain sensation in IBS-like mouse model and to explore regulatory mechanisms of nerve fiber elongation caused by serotonin and neurotrophic factors in human neuroblastoma SHSY5Y cells.
Method：Two IBS-like mouse models, one is dual trigger of post- infection combined with water avoidance stress (GW), and the other one is post-inflammatory of TNBS-induced colitis (PT). The Ctrl or PT mice were given serotonin receptor compounds by oral or intraperitoneal injection for measurement of colorectal distension-visceromotor response (CRD-VMR) and charcoal meal test. Immunofluorescence (IF) staining of PGP9.5 (a pan-neuron marker) and serotonin receptors were conducted in mouse colonic tissues. Human neuroblastoma SH-SY5Y cells were incubated with GW and PT mouse colonic supernatant, serotonin and neurotrophic factor to stimulate nerve fiber elongation and to observe the gene expression. Lastly, colonic biopsies of IBS patients and healthy controls were collected to examine mucosal nerve distribution and serotonin receptors (5-HT3R, 5-HT4R and 5-HT7R). Result：Oral administration of a specific serotonin receptor ligand (CYY1005) reduced the visceral hypersensitivity in the PT mice, but did not affect normal pain sensation in control mice. PT mice were intraperitoneal administered serotonin receptor compounds (CYY073、CYY1280-3、CYY1294), and only CYY1280-3 can significantly decrease visceral hypersensitivity. By immunofluorescence staining, higher PGP9.5 and serotonin receptor immunoreactivity was found in the colonic mucosa of GW and PT mice compared to control mice, and those in IBS patients were higher than healthy controls. Pretreatment with serotonin receptor ligand (CYY1005) or 5-HT7R antagonist (SB7) inhibited the induction of nerve fiber outgrowth by GW and PT mouse colonic supernatant, serotonin and neurotrophic factor in SH-SY5Y cells. Lastly, the mRNA expression levels of p75NTR, TrkA, TrkB, and serotonin receptor of SH-SY5Y cells were significantly increased by neurotrophic factors. Conclusion：Our data showed that serotonin receptor was involved in the visceral hypersensitivity response in PT mice. In addition, serotonin and neurotrophic factors regulated nerve fiber elongation. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T15:11:55Z (GMT). No. of bitstreams: 1 ntu-108-R06441013-1.pdf: 4540600 bytes, checksum: dc0610c4fb6191fe815a75ad51c09f4e (MD5) Previous issue date: 2019 | en |
| dc.description.tableofcontents | 致謝……............................................................................................................................I
摘要……………………………………………………………………………………...II Abstract………………………………………………………………………………...IV 目錄………………………………………………………………………………….…VI 圖目錄……………………………………… X 壹、 前言 1 1. 神經系統對腸道功能之調控 1 2. 內臟痛覺傳遞途徑 2 2.1上行痛覺傳遞(Ascending visceral pain pathway) 2 2.2下行痛覺傳遞(Descending visceral pain pathway) 2 3. 雙向腦腸軸(bidirectional brain-gut axis) 3 4. 腸躁症(Irritable bowel syndrome, IBS) 4 4.1流行病學 4 4.2危險因子探討 4 4.2.1精神壓力 5 4.2.2腸道病原體感染 5 4.2.3慢性腸道發炎 6 4.3類腸躁症動物模式 7 4.3.1避水行為誘發精神壓力模式 7 4.3.2梨形鞭毛蟲感染排除後模式 8 4.3.3三硝基苯黃酸誘導發炎復原模式 9 5. 內臟高敏感性(visceral hypersensitivity)及相關分子機制 10 5.1離子通道及痛覺受器表現量改變 11 5.2神經內分泌物質產量及其接受器的表現量改變 12 5.3神經營養因子表現量改變 14 6. 腸躁症內臟高敏感性與神經細胞功能型態關聯性 16 7. 人類神經母細胞瘤SHSY5Y細胞株作為神經分化與纖維生長的模式 16 8. 研究目的 17 貳、 材料與方法 18 1. 實驗動物 18 2. 後腸炎性類腸躁症模式(Post-TNBS, PT) 18 2.1三硝基苯磺酸(2,4,6-trinitrobenzenesulfonic acid solution,TNBS)誘導小鼠結腸炎模式 18 3. 血清素受器化合物與測試 20 3.1參考標準品(Reference Standard) 20 3.2新合成血清素受器化合物 20 3.3藥物試驗流程 20 3.3.1單一劑量(single dose, s.d.)藥物給予 21 3.3.2多重劑量(multiple dose, m.d.)藥物給予 21 4. 結直腸撐張刺激-內臟動器反應分析(Colorectal distension-Visceromotor response, CRD-VMR) 22 5. 活性碳試驗(charcoal meal test)之腸道蠕動性 24 6. 組織切片與染色 24 6.1冷凍包埋檢體 24 6.2免疫螢光染色(Immunofluorescence, IF) 24 7. 神經細胞實驗 25 7.1 SH-SY5Y細胞株 25 7.2神經纖維生長(neurite outgrowth)實驗 26 7.2.1腸道組織上清液刺激 26 7.2.2血清素刺激 27 7.2.3血清素第七型受器促進劑(5-HT7 receptor agonist)刺激 27 7.2.4神經營養因子刺激 28 7.2.5 雙重因子刺激 29 7.2.6 抑制劑實驗(blockade experiments)和半抑制濃度( IC50)測定 30 7.3腸組織無菌上清液(bacteria-free gut supernatant)製備 32 7.4細胞影像攝影與神經細胞纖維長度測量 32 8. 人體大腸黏膜檢體收集 33 9. 核糖核酸(mRNA)測定 34 9.1萃取細胞核糖核酸技術 34 9.2反轉錄聚合酶連鎖反應(Reverse Transcription Polymerase Chain Reaction, RT-PCR) 35 9.3即時聚合酶連鎖反應(Real time polymerase chain reaction, real-time PCR) 35 10. 統計方法 36 參、 實驗結果 36 一、 後腸炎性類腸躁症模式(Post-TNBS, PT) 與正常對照組(Control, Ctrl)動物中血清素受體對於腸道痛覺的影響 36 1.經口給予單一劑量血清素受器配體對Ctrl及PT組小鼠痛覺與蠕動的影響 37 2.經口給予多重劑量血清素受器配體對Ctrl及PT組小鼠痛覺與蠕動的影響 37 3.腹腔注射給予單一劑量的不同血清素受器配體對PT小鼠痛覺與蠕動的影響 37 二、 後感染合併避水壓力(GW)與後腸炎性(PT)類腸躁症小鼠模式 38 1.後感染合併避水壓力(GW)小鼠模式 38 1.1神經蛋白基因產物9.5(PGP9.5)在腸道黏膜中的表現 38 1.2血清素第七型受體受器(5-HT7R)在腸道黏膜中的表現 38 2.後腸炎性(PT)小鼠模式 39 2.1神經蛋白基因產物9.5(PGP9.5)在腸道黏膜中的表現 39 2.2血清素第七型受體受器(5-HT7R)在腸道黏膜中的表現 39 三、 腸躁症患者大腸黏膜層中神經及血清素受器分佈 39 1.腸道組織中神經(PGP9.5)分布及表現 39 2.腸道組織中血清素第七型受體(5-HT7R)分布 40 3.腸道組織中血清素第三型受體(5-HT3R)分布 40 4.腸道組織中血清素第四型受體(5-HT4R)分布 40 5.腸道組織中神經(PGP9.5)與第七型受體(5-HT7R)共定位分布表現 40 四、 利用SH-SY5Y神經細胞探討神經纖維延長 40 1.GW小鼠腸道上清液對SH-SY5Y神經纖維延長影響 41 1.1血清素受器配體之劑量依賴性 41 1.2參考標準品SB7(血清素第七型受器拮抗劑)之劑量依賴性 41 1.3比較兩種血清素受器配體對於GW小鼠腸道上清液刺激的半抑制濃度(IC50) 42 2.PT小鼠腸道上清液對SH-SY5Y神經纖維延長影響 42 2.1血清素受器配體之劑量依賴性 42 2.2參考標準品SB7(血清素第七型受器拮抗劑)之劑量依賴性 43 2.3比較兩種血清素受器配體對於PT小鼠腸道上清液刺激的半抑制濃度(IC50) 44 3.血清素對SH-SY5Y神經細胞纖維延長影響 44 3.1血清素受器配體之劑量依賴性 44 3.2 參考標準品SB7(血清素第七型受器拮抗劑)之劑量依賴性 45 3.3比較兩種血清素受器配體對於血清素刺激的半抑制濃度(IC50) 45 3.4 LP-211 (5-HT7R促進劑)對SH-SY5Y神經細胞纖維延長的影響 45 4.神經營養因子對SHSY5Y神經纖維延長的影響 46 4.1 BDNF對SH-SY5Y神經纖維延長機制中血清素受器配體的角色 46 4.2測試神經生長因子NGF對SH-SY5Y神經細胞纖維延長的效果 47 4.3 NGF對SH-SY5Y神經纖維延長機制中血清素受器配體的角色 47 4.4探討NGF和BDNF合併給予對SH-SY5Y神經纖維延長之影響 48 4.5探討BDNF與血清素合併給予對SH-SY5Y神經纖維延長之影響 48 4.6探討NGF與血清素合併給予對SH-SY5Y神經纖維延長之影響 49 5.神經營養因子調控SH-SY5Y 細胞中特定基因的表現量 49 肆、 討論 50 伍、 參考文獻 93 | |
| dc.language.iso | zh-TW | |
| dc.subject | 血清素受器 | zh_TW |
| dc.subject | 腸炎 | zh_TW |
| dc.subject | 內臟高敏感性 | zh_TW |
| dc.subject | 血清素 | zh_TW |
| dc.subject | 神經營養因子 | zh_TW |
| dc.subject | 腸躁症 | zh_TW |
| dc.subject | neurotrophic factors. | en |
| dc.subject | Irritable bowel syndrome | en |
| dc.subject | colitis | en |
| dc.subject | visceral hypersensitivity | en |
| dc.subject | serotonin | en |
| dc.subject | serotonin receptor | en |
| dc.title | 神經營養因子刺激神經纖維生長在腸道疼痛感覺中所扮演的角色 | zh_TW |
| dc.title | Roles of Neurotrophins in Neurite Outgrowth and Intestinal Pain Sensation. | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 107-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 忻凌偉,吳明賢 | |
| dc.subject.keyword | 腸躁症,腸炎,內臟高敏感性,血清素,血清素受器,神經營養因子, | zh_TW |
| dc.subject.keyword | Irritable bowel syndrome,colitis,visceral hypersensitivity,serotonin,serotonin receptor,neurotrophic factors., | en |
| dc.relation.page | 101 | |
| dc.identifier.doi | 10.6342/NTU201902329 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2019-08-06 | |
| 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 | 2029-12-31 | - |
| 顯示於系所單位： | 生理學科所 | |
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