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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 楊性芳(Hsin-Fang Yang-Yen) | |
| dc.contributor.author | Pei-Hsuan Chia | en |
| dc.contributor.author | 賈佩璇 | zh_TW |
| dc.date.accessioned | 2021-06-15T02:57:23Z | - |
| dc.date.available | 2010-09-15 | |
| dc.date.copyright | 2009-09-15 | |
| dc.date.issued | 2009 | |
| dc.date.submitted | 2009-08-01 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/44434 | - |
| dc.description.abstract | Mcl-1屬於Bcl-2蛋白家族中具有抗細胞凋亡功能的一員，在諸多受調控的細胞生死程式中扮演重要的上游角色。老鼠若全身性缺乏Mcl-1蛋白，會造成胚胎在著床前後死亡。在這篇論文中，我們利用Cre-loxP系統將內皮細胞譜系中的mcl-1基因剔除。以Tie2-cre將內皮細胞部份的mcl-1剔除後，會造成大部分的胚胎死亡：Tie2-cre;mMcl-1f/ko突變鼠的比例從E13.5以後開始明顯下降，但有部分突變鼠可以存活到出生後。組織切片分析顯示，這些條件性基因剔除小鼠的心臟發育有嚴重的延遲現象，其中ㄧ隻還帶有與先天性心臟缺損相似的缺陷。然而，再經由更細部的分析之後，我們未能在Tie2-cre;mMcl-1f/ko突變鼠的心內膜墊(endocardial cushion)中觀察到不正常的間葉細胞(mesenchymal cell)增生或凋亡亦或是神經脊細胞(neural crest cell)遷移的異常。存活的Tie2-cre;mMcl-1f/ko突變鼠經由心臟超音波檢查發現，主動脈血液回流以及和主動脈狹窄相似的表現型。這些結果暗示了內皮細胞所表現的Mcl-1蛋白在胚胎心臟發育和維持成熟心臟的正常功能中扮演了重要的角色。我們仍然需要更多的實驗來說明Mcl-1蛋白如何實行這些功能。 | zh_TW |
| dc.description.abstract | Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 protein family, which plays an apical role in many regulatory programs of cell death and survival. Mcl-1 deficiency results in peri-implantation lethality. Here, we employed the Cre-loxP system to conditionally knockout mcl-1 in the endothelial cell lineage. Tie2-cre-mediated deletion of mcl-1 leads to embryonic lethality with incomplete penetrance, with the expected frequency of Tie2-cre;mMcl-1f/ko conditional knockout embryos decreasing dramatically after E13.5. Histological analysis revealed that these conditional knockout embryos demonstrate a severe delay in heart development and one of them manifested defects mimicking congenital heart defects. However, detailed analysis revealed that cell proliferation and survival of mesenchymal cells in the endocardial cushion as well as migration of neural crest cell appeared to be normal in these mutant mice. The survived adult conditional knockout mice showed aortic regurgitation and an aortic stenosis-like phenotype. These results suggest a crucial role of endothelial Mcl-1 in embryonic heart development and maintaining normal heart functions during the adulthood. How Mcl-1 carries out these functions remains to be determined. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T02:57:23Z (GMT). No. of bitstreams: 1 ntu-98-R96448011-1.pdf: 2566806 bytes, checksum: aabb1f2293a1b888198904d2035379b9 (MD5) Previous issue date: 2009 | en |
| dc.description.tableofcontents | Table of content………………………………………...……………………………….1
中文摘要………………………………………………………………………………...6 Abstract……………………..………………………………………………………......7 1. Introduction…………………………………………………………………...……...8 1-1 Mcl-1 (Myeloid cell leukemia-1)…………………………………………………8 1-1-1 Structure of Mcl-1…………………………………………………………..8 1-1-2 Regulation of Mcl-1 expression………………………………………….....9 1-1-3 Regulation of Mcl-1 protein stability……………………………………...11 1-1-4 Biological functions of Mcl-1……………………………………………..11 1-1-5 Mcl-1 expression in endothelial cells……………………………………..13 1-2 Cre-loxP system…………………………………………………………………13 1-3 Tie2………………………………………………………………………………15 1-3-1 Identification and characterization of Tie2………………………………..15 1-3-2 Expression of Tie2………………………………………………………...16 1-3-3 Tie2-cre transgenic mice…………………………………………………..18 1-4 Heart development………………………………………………………………19 1-5 Specific aims…………………………………………………………………….22 2. Material and methods……………………………………………………….……..24 2-1 Mouse (Mus musculus) strains……………………………………………….….24 2-2 Generation of Conditional knockout embryos……………………………….….24 2-3 Genotyping…………………………………………………………………..…..25 2-4 Histology and Immunohistochemistry………………………………………..…26 2-5 LacZ Staining………………………………………………………………..…..27 2-6 Cell Proliferation Analysis………………………………………………..……..28 2-7 Cell Apoptosis Analysis……………………………………………………..…..29 2-8 RNA In Situ Hybridization………………………………………………..…….29 2-9 Image Acquisition…………………………………………………………...…..31 3. Results…………………………………………………………………………...…..33 3-1 Mcl-1 expression patterns in the mouse heart region…………………………....33 3-2 Disruption of the mcl-1 gene in endothelial cells……………………………….33 3-3 Embryos lacking Mcl-1 in endothelial cell lineage have heart defects………….35 3-4 Embryos lacking one allele of the gene mcl-1 in endothelial cells have heart defects………………………………………………………………………...….36 3-5 Disruption of Mcl-1 expression in the endothelial cell lineage results in a decrease in mesenchymal cell number in endocardial cushions…………………38 3-6 Cardiac neural crest cell migration in endothelial cell Mcl-1 deficient embryos………………………………………………………………………….39 3-7 Regurgitation of the aortic semilunar valve in Mcl-1 conditional knockout mice………………………………………………………………………..…….40 4. Discussion……………………………………...……………………………..……..42 4-1 Endothelial cell Mcl-1 may be required for embryonic hematopoiesis………....43 4-2 Mcl-1 expressed in the endothelial cell lineage is essential for embryonic heart development………………………………………………………………..…….44 4-3 Endothelial cell Mcl-1 is a dosage-sensitive regulator of cardiac morphogenesis…………………………………………………………………...46 4-4 Depletion of Mcl-1 in endothelial cell results in an aortic stenosis-like phenotype………………………………………………………………………...47 5. Figures and tables………………………………………………………………..…49 Figure 1. Transverse sections of E12.5 mMcl-1f/+ embryos were immunohistochemically stained with mouse Mcl-1-specific antibodies………...49 Figure 2. Schematic respresentation of the mcl-1 locus, targeting vector, mcl-1 flox allele and mcl-1 deletion allele………………………………………………….50 Figure 3. Schematic representation of the mcl-1 genome locus, targeting vector and the mutant alleles……………………………………………………………...…51 Figure 4. X-gal stained transverse sections of Tie2-cre; R26R transgenic E11.5 embryos………………………………………………………………………….52 Figure 5. Mating strategy of this study………………………………………………53 TABLE 1. Survival analysis of embryos and postnatal pups derived from Tie2-cre;mMcl-1+/ko crossed with mMcl-1f/f mice……………………………….54 Figure 6. Live embryos dissected at E10.5…………………………………………..55 Figure 7. Live embryos dissected at E11.5…………………………………………..56 Figure 8. Live embryos dissected at E13.5, E14.5 and E15.5……………………….57 Figure 9. Developmental delay of Tie2-cre;mMcl-1f/ko mutants…………………….58 Figure 10. OFT alignment defects in Tie2-cre;mMcl-1f/ko mutants………………….59 Figure 11. VSD and right atrial dilation in Tie2-cre;mMcl-1f/ko mutants……………60 Figure 12. Dilation of atria and developmental delay in mMcl-1f/ko hypomorphic mutants……………………………………………………………………….…..61 Figure 13. OFT alignment defects, VSD and right atrial dilation in mMcl-1f/ko hypomorphic mutants…………………………………………………………....62 TABLE 2. Frequency of cardiovascular defects in E13.5 embryos from various genotyoes……………………………………………………………………...…63 Figure 14. Transverse sections of control, mMcl-1f/ko and Tie2-cre;mMcl-1f/ko E12.5 embryos were Immunohistochemically stained with mouse Mcl-1-specific antibodies………………………………………………………………………...64 Figure 15. Loss of Mcl-1 in endothelial cells reduces the cell number of mesenchymal cell in endocardial cushions……………………………………....65 Figure 16. Loss of Mcl-1 in endothelial cells does not affect proliferation of mesenchymal cell in the endocardial cushions…………………………………..66 TABLE 3. Quantitative results of TUNEL staining in E10.5 and E11.5 embryos…..67 Figure 17. Neural crest cell (NCC) migration in Mcl-1 conditional knockout mice. Whole-mount in situ hybridization of embryos at E10.5 using Crabp1-specific probe…………………………………………………………………………..…68 Figure 18. The survived Tie2-cre;mMcl-1f/ko mice did not manifest any defects in heart contraction…………………………………………………………………69 TABLE 4. Comparison of LV Diastolic Inflow Parameters…………………………70 Figure 19. Aortic semilunar valve regurgitation revealed by color flow Doppler recording in 9-month-old mMcl-1f/ko, Tie2-cre;mMcl-1f/+ and Tie2-cre;mMcl-1f/ko mice………………………………………………………...................................71 TABLE 5. Results of Parameters Scored in the Echocardiographic Recording……..72 Figure 20. The vascular system in yolk sacs of Tie2-cre;mMcl-1f/ko embryos at E9.5 is under-developed…………………………………………………………………73 Reference…………………………………………………………………………...….74 | |
| dc.language.iso | en | |
| dc.subject | 心臟發育 | zh_TW |
| dc.subject | Mcl-1 | zh_TW |
| dc.subject | 細胞凋亡 | zh_TW |
| dc.subject | 內皮細胞譜系 | zh_TW |
| dc.subject | 小鼠 | zh_TW |
| dc.subject | anti-apoptotic member | en |
| dc.subject | endothelial cell lineage | en |
| dc.subject | Cre-loxP system | en |
| dc.subject | Mcl-1 | en |
| dc.subject | heart development | en |
| dc.title | 促存活蛋白Mcl-1在Tie2+細胞譜系之功能探討 | zh_TW |
| dc.title | Functional Characterization of the Pro-survival Protein Mcl-1 in Tie2+ Cell Lineage | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 97-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 游麗如(Li-Ru You),吳君泰(June-Tai Wu) | |
| dc.subject.keyword | Mcl-1,細胞凋亡,內皮細胞譜系,小鼠,心臟發育, | zh_TW |
| dc.subject.keyword | Mcl-1,anti-apoptotic member,Cre-loxP system,endothelial cell lineage,heart development, | en |
| dc.relation.page | 80 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2009-08-03 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
| 顯示於系所單位： | 分子醫學研究所 | |
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