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研究生:梁晴閔
研究生(外文):Liang, Ching-Min
論文名稱:研究 CADASIL疾病模型Notch3R545C小鼠內皮細胞與壁細胞的相互作用
論文名稱(外文):Study the interaction of endothelial cells and mural cells in the CADASIL disease modeling Notch3R545C mouse
指導教授:楊良棟李佳霖李佳霖引用關係
指導教授(外文):Yang, Liang-TungLee, Jia-Lin
口試委員:李宜中黃玠誠
口試委員(外文):Lee, Yi-ChungHuang, Chieh-Cheng
口試日期:2023-12-14
學位類別:碩士
校院名稱:國立清華大學
系所名稱:分子與細胞生物研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2023
畢業學年度:112
語文別:英文
論文頁數:70
中文關鍵詞:CADASILNoctchR544C小血管疾病缺血性腦中風NOTCH 信號通路周細胞內皮細胞
外文關鍵詞:CADASILNoctchR544Cp.Arg544Cyssmall vessel diseaseischemic strokeNOTCH signaling pathwaypericytesendothelial cells
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CADASIL(體顯性腦動脈血管病變合併皮質下腦梗塞及腦白質病變)是一種 由 NOTCH3 基因突變引起的單基因遺傳性小血管疾病。NOTCH3 p.Arg544Cys 突 變是常見於台灣人基因的 CADASIL 致病突變,目前有超過 70%的台灣 CADASIL 病患帶有此 p.Arg544Cys 突變。NOTCH3 p.Arg544Cys 突變位於 NOTCH3 的胞外結 構域中 EGF-like repeats(EGFR)13 和 14 的交界處,此位置靠近 NOTCH3 與其配 體的結合位點 EGFR 11-12。NOTCH 信號通路還參與血管生成的調控、血管穩態的 維持和血管通透性屏障。有鑒於人類 NOTCH3 p.Arg544Cys 突變的位置,我們推測 小鼠的 NOTCH3 p.R545C 突變可能直接影響受體與配體的結合,導致周細胞與內 皮細胞間異常的相互作用,並從而導致血管功能的缺陷。
在本研究中,我們探討了 NOTCH3WT 和 NOTCH3R545 在受體-配體的結合效率 和配體誘導之訊號活性,以及 Notch3WT 野生型和 Notch3R545 突變型兩種小鼠之周細 胞的細胞功能。我們在過表現研究中觀察到 NOTCH3R545C 表現較低的配體結合效 率以及配體誘導之 NOTCH 信號通路的活性,在初代細胞研究中,我們也觀察到野 生型周細胞比 p.Arg545Cys 突變型周細胞能更好的支持血管新生、維持血管穩定度 以及支持更好的血管屏障功能。整體來說,我們的數據表明 NOTCH3 p.Arg544Cys 突變可能對血管穩態產生負面影響。
CADASIL (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a hereditarily monogenic small vessel disease (SVD) caused by mutations in NOTCH3 gene. NOTCH3 p.Arg544Cys mutation is a common mutation that causes CADASIL in Taiwan— more than 70% of the diseased Taiwanese population carry the R544C mutation. The NOTCH3 p.Arg544Cys mutation locates at the boundary of EGF-like repeats (EGFR) 13 and 14 in the extracellular domain of NOTCH3, which is close to the ligand-binding site EGFR 11-12. NOTCH signaling is involved in the modulation of angiogenesis, vascular homeostasis, and vascular permeability barrier. Given the location of human NOTCH3 p.Arg544Cys mutation, we speculate that the murine NOTCH3 p.Arg545Cys mutation directly impacts the binding of ligand-receptor and causes the abnormal cell-cell interactions between mural cells and endothelial cells, which leads to deficits in vascular function.
In this study, we measure the ligand-binding efficiency, ligand-induced signal activity of NOTCH3WT and NOTCH3R545C, and also the biological function of mural cells from Notch3WT and Notch3R545C mice. In the overexpression study, NOTCH3R545C displays reduced ligand-binding efficiency and ligand-induced NOTCH signal activity. In the primary cell study, we also observed that the NOTCH3WT mural cells support the angiogenesis, maintain vessel stability and barrier function better than NOTCH3R545C mural cells. Overall, our data suggest that NOTCH3 p.R544C mutation could generate a negative impact on the blood vessel homeostasis.
Abstract...I
中文摘要 ... II
致謝... III
Table of Contents...IV
Chapter 1. Introduction...1
1.1 CADASIL...1
1.2 NOTCH signaling...2
1.3 Cerebral small vascular system...4
1.4 NOTCH3 signaling in the blood vessel formation ... 6
1.5 Aim ... 7
Chapter 2. Materials and Methods...9
2.1 Experiment design ... 9
2.2 Reagent... 11
2.3 Animal ... 13
2.4 Cell line and cell culture ... 13
2.5 Antibody and fluorescent dye ... 14
2.6 DNA construct ... 14
2.7 Transfection ... 15
2.8 Immunocytochemistry (ICC)...15
2.9 Production of Delta-Fc soluble ligand...16
2.10 Soluble ligand binding assay in overexpression study and primary cell study... 17
2.11 NOTCH3 cell surface expression assay... 18
2.12 Dual-Luciferase reporter assay...19
2.13 JAGGED1 expressing-Swiss 3T3 stable cell line...20
2.14 Western blotting ... 20
2.15 Isolation of mice brain pericytes...20
2.16 Tube formation assay... 22
2.17 Trans-endothelial Electrical Resistance (TEER)...23
2.18 Vascular permeability assay... 24
Chapter 3. Results... 25
3.1 NOTCH3 and JAGGED1 binding through cell-cell interaction ... 25
3.2 The p.R545C mutation may reduce the ligand binding efficiency... 25
3.3 The p.R545C mutation reduces the ligand-induced NOTCH signal activity...27
3.4 Immunocytochemical characterization of pericyte cultures and bEND3 cell line ... 28
3.5 Notch3WT and Notch3R545C mural cells display no significant difference in ligand binding efficiency... 30
3.6 Notch3WT mural cells promote angiogenesis better than Notch3R545C mural cells. ... 31
3.7 Notch3R545C mural cells display declined barrier function... 32
3.8 Conclusion... 33
Chapter 4. Discussion ... 34
4.1 The later symptom-onset in Taiwanese population might relate to the moderate impacts of the p.Arg544Cys mutation... 34
4.2 The functional assays... 36
4.3 Behavioral assessment of the neurodegenerative function of Notch3R545C CRISPR-edited homozygous knock-in mice...38
Figures and Tables ... 39
Figure.1 MRI T2 white matter abnormalities in CADASIL patients... 39 Figure.2 Process of the five main clinical manifestations of CADASIL... 39
Figure.3 NOTCH signaling pathway in mammals...40
Figure.4 Structures of NOTCH3 receptor and JAGGED1 ligand... 41
Figure.5 Location of the p.R544C mutation ... 42
Figure.6 Chart of experiment design...43
Figure.7 Schematic diagram of soluble ligand binding assay of 293T cell... 43
Figure.8 Schematic diagram of NOTCH3 cell surface expression assay of 293T cell... 44
Figure.9 Schematic diagram of The Dual-Luciferase® Reporter (DLRTM) Assay System... 44
Figure.10 Measure the cell-cell interaction of NOTCH3 and JAGGED1 binding... 45
Figure.11 The p.R545C mutation may reduce the ligand binding efficiency... 46
Figure.12 JAGGED1 ligand-induced NOTCH3 signal activity...49
Figure.13 Characterization of adult brain pericyte cell culture... 50 Figure.14 Characterization of endothelial cell line bEND3... 51 Figure.15 Characterization of neonatal pericyte cell culture... 53 Figure.16 Notch3WT and Notch3R545C mural cells display no significant difference in ligand binding efficiency... 54
Figure.17 Analysis of angiogenic potential of bEND3 cells with Notch3WT or Notch3R545C pericytes by in vitro Tube Formation Assay... 56
Figure.18 Notch3WT and Notch3R545C mural cells display no significant difference in barrier formation and barrier function through TEER assay.... 59
Figure.19 Notch3R545C mural cells display declined barrier function through vascular permeability assay... 60
Figure.20 JAGGED1 stable-ligand-induced NOTCH3 signal activity...61
Table.1 Primary antibodies used in this study...62
Table.2 Secondary antibodies used in this study... 63
Table.3 Fluorescent dyes used in this study... 63
Table.4 Common cell markers for brain cells... 64
Reference... 65
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