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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳青周(Ching-Chow Chen) | |
| dc.contributor.author | Yi-Ting Lin | en |
| dc.contributor.author | 林怡亭 | zh_TW |
| dc.date.accessioned | 2021-07-11T14:56:45Z | - |
| dc.date.available | 2025-03-13 | |
| dc.date.copyright | 2020-03-13 | |
| dc.date.issued | 2020 | |
| dc.date.submitted | 2020-02-17 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78433 | - |
| dc.description.abstract | CREB結合蛋白(CBP)為轉錄輔助因子，具組蛋白乙醯轉移酶活性，利於轉錄因子與DNA之結合而增加基因之轉錄。我們先前之研究發現，IKKalpha磷酸化CBP Ser1382/1386位點，會抑制與p53之結合而調控細胞命運。CBP-AA-knock-in 小鼠是將CBP Ser1383/1387位點置換成alanine (AA)，造成腸道表皮細胞之恆定缺失，導致成鼠之自發性腸炎。腸道屏障功能受損，包括腸通透性增加、腸道表皮細胞凋亡、腸道幹性減少和腸道表皮細胞自我更新延遲。臨床潰瘍性結腸炎患者也觀察到低度表現磷酸化CBP。此外，CBP磷酸化受損亦會造成腸道菌叢之失衡，伴隨致腸炎菌叢Proteobacteria增加。AA小鼠對外來刺激(DSS)具高度敏感性，其腸炎症狀經由與WT小鼠共養，菌叢之交換而減輕其症狀，其中Akkermansia菌叢之改變最為明顯。這些證據顯示，CBP磷酸化受損會造成腸上皮屏障損傷、菌相失衡及對外來刺激之高敏感，說明其在腸道表皮細胞恆定之調控扮演重要角色，可作為發炎性腸道疾病之新穎研究平台。期能由AA小鼠找到腸炎致病理之更詳細機轉，以期發展新的疾病治療策略。 | zh_TW |
| dc.description.abstract | CREB-binding protein (CBP) is a transcriptional coactivator regulating DNA accessibility to modulate a variety of cellular functions. Phosphorylation of human CBP by IKKalpha at Ser1382/1386 plays a critical role in the regulation of cell fate by suppressing p53-mediated gene expression. CBP-AA-knockin mice replacing CBP Ser1383/1387 with alanines (AA) exhibit a spontaneous colitis phenotype instigated by impaired phosphorylation of CBP in non-hematopoietic cells origin. The disturbed colonic epithelial homeostasis was characterized by hyperpermeability, apoptosis, reduced stemness and delayed turnover of epithelial cells. Clinical relevance was shown by reduced phosphorylated CBP in colonic biopsies from patients with ulcerative colitis. Impaired phosphorylation of CBP in mice also caused gut dysbiosis associated with a greater abundance of colitogenic strain (of the phyla Proteobacteria). AA mice were more susceptible to external stimulator such as DSS. This phenomenon was abolished by microbiota-transfer strategy in cohousing settings. The greatest change in cohousing after DSS treatment was the transfer of genus Akkermansia from AA mice to WT mice. Our unique AA mouse model provides compelling evidences to demonstrate that impaired CBP phosphorylation in non-hematopoietic compartment drives spontaneous colitis and gut dysbiosis, and is enhanced by external stimulator, revealing a clinically relevant mechanism of IBD and shedding light on the management of bowel disorders. This study unveils the significance of basic molecular mechanism for an important disease in humans. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T14:56:45Z (GMT). No. of bitstreams: 1 ntu-109-D03443001-1.pdf: 8163199 bytes, checksum: ee08c9d2a79b3dbec8dc7b5a68e23b57 (MD5) Previous issue date: 2020 | en |
| dc.description.tableofcontents | Abbreviation 2
中文摘要 4 Abstract in English 5 Chapter I. Introduction 6 1. Inflammatory bowel disease 6 2. Intestinal homeostasis 9 3. CREB-binding protein (CBP) 20 4. Microbiota 29 5. Experimental rationale 42 Chapter II. Materials and Methods 43 Chapter III. Results and Discussion 58 Part 1. Impaired phosphorylation of CBP leads to colitis through disturbances of intestinal homeostasis 58 Part 2. Impaired phosphorylation of CBP leads to colitis through disturbances of intestinal microbiota 93 Chapter IV. Conclusion and Perspective 105 References 106 Appendix 118 Publications and Honors 124 | |
| dc.language.iso | en | |
| dc.subject | 發炎性腸炎 | zh_TW |
| dc.subject | 腸道菌 | zh_TW |
| dc.subject | 菌相失衡 | zh_TW |
| dc.subject | CREB結合蛋白 | zh_TW |
| dc.subject | 腸道屏障 | zh_TW |
| dc.subject | 發炎 | zh_TW |
| dc.subject | 結腸炎 | zh_TW |
| dc.subject | intestinal barrier function | en |
| dc.subject | microbiota | en |
| dc.subject | inflammation | en |
| dc.subject | dysbiosis | en |
| dc.subject | CBP | en |
| dc.subject | IBD | en |
| dc.subject | colitis | en |
| dc.title | CBP磷酸化缺失導致腸道屏障及菌叢失衡而引發小鼠腸炎之研究 | zh_TW |
| dc.title | Impaired phosphorylation of CBP leads to colitis through disturbances of intestinal homeostasis and microbiota | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 108-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 繆希椿(Shi-Chuen Miaw),吳明賢(Ming-Shiang Wu),徐志文(Jr-Wen Shui),蔡丰喬(Feng-Chiao Tsai),黃偉謙(Wei-Chien Huang) | |
| dc.subject.keyword | 發炎性腸炎,結腸炎,發炎,腸道屏障,CREB結合蛋白,菌相失衡,腸道菌, | zh_TW |
| dc.subject.keyword | IBD,colitis,inflammation,intestinal barrier function,CBP,dysbiosis,microbiota, | en |
| dc.relation.page | 125 | |
| dc.identifier.doi | 10.6342/NTU202000483 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2020-02-17 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥理學研究所 | zh_TW |
| dc.date.embargo-lift | 2025-03-13 | - |
| 顯示於系所單位： | 藥理學科所 | |
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