系統識別號 U0026-2701201216195400
論文名稱(中文) 探討血管生成相關基因在習慣性流產的角色
論文名稱(英文) The role of VEGF, EG-VEGF and their receptors in recurrent pregnancy loss: genetic association studies and functional characterization of genetic variants
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 100
學期 1
出版年 101
研究生(中文) 蘇美慈
研究生(英文) Mei-Tsz Su
學號 S9895110
學位類別 博士
語文別 英文
論文頁數 85頁
口試委員 指導教授-郭保麟
中文關鍵字 血管生成  習慣性流產 
英文關鍵字 recurrent pregnancy loss  VEGF  EG-VEGF 
中文摘要 習慣性流產的定義為懷孕20週前的連續性流產,流行病學上約占1-5%的受孕婦女。習慣性流產受很多因子的影響而導致,但經由臨床的各種檢查後仍然有一半以上的習慣性流產婦女查不出致病的原因, 而基因的多型性提供這群原因不明的習慣性流產病人可能增加流產的原因。血管生成對於早期的懷孕有很重要的角色,包含: 卵子的成熟、黃體期的子宮內膜發育、胚胎的著床、胚胎的發育及胎盤功能的維持。臨床上及動物實驗都顯示血管生成及血流的充足對於胚胎著床及早期懷孕的重要性。在習慣性流產的病人的基因晶片報告中, 顯示其姙娠組織之一些血管生成相關的基因表現有下降的現象。儘管臨床上及動物實驗都顯示血管生成相關基因對於胚胎著床及早期懷孕的重要性,但對於基因多型性及haplotype鮮少有人報導,在台灣的漢族婦女更缺乏這方面的資料,於是本論文設定四個目標要探討血管生成相關基因對於早期懷孕的影響: (1) VEGF及其受體(KDR)的基因多型性是否與台灣女性的習慣性流產有相關。(2) EG-VEGF及其受體(PKR1, PKR2)的基因多型性是否與台灣女性的習慣性流產有相關。(3)根據目標二的資料,利用定序方式找出在PKR1, PKR2的基因編碼區可能影響習慣性流產的基因位點。(4)利用in vitro assays印證可能影響的基因位點對功能所造成的改變。在本研究中有以下的發現 (1)一個變異的KDR位點(Q472H)顯著地與習慣性流產相關,且VEGF及KDR的haplotypes也顯著地與習慣性流產相關。(2)藉由tag SNPs的方式發現: PKR1及PKR2的基因多型性顯著地與習慣性流產相關,且兩受體基因與EG-VEGF可能存在基因間的交互作用。(3)根據目標二的資料,利用基因定序方式發現: PKR1及PKR2各有一可能的基因變異點 (I379V, V331M)可能影響早期的懷孕。(4)在進一步的功能性研究發現PKR1(I379V)及PKR2 (V331M)皆可改變細胞內鈣離子的濃度及細胞的侵犯能力。總結本研究的結果, KDR, PKR1/2 的基因多型性及VEGF, KDR,PKR1/2的haplotypes皆與習慣性流產相關;PKR1/2的基因變異可能藉由改變鈣離子的通透及增加細胞的侵犯能力而有利於胚胎的著床及接近養分及氧氣充足的區域,進而降低習慣性流產的機會。
英文摘要 Recurrent pregnancy loss (RPL) is the occurrence of repeated abortion before 20 weeks of gestation, and it affects about 1-5% of women who conceive. RPL is a multi-factorial disorder and up to 50% of cases remain undetermined causes after detailed clinical examination. In patients with idiopathic RPL, gene polymorphisms have been proposed as susceptibility factors that increase the risk of pregnancy loss. Angiogenesis is critical in several stages of human pregnancy, including oocyte maturation, decidulaized endometrial vascularization, embryo implantation/ development and placenta angiogenesis/ vascularization. A decreased expression pattern of angiogenesis-related genes in the chorionic villi of RPL patients was ever reported in a microarray study. Although angiogenesis plays such an important role in early pregnancy, little information on gene polymorphisms of angiogenesis-related genes was reported to be associated with RPL, especially the data of Taiwanese Han women. Four specific aims were set to explore the effects of angiogenesis-related genes on human early pregnancy: (1) To explore the association between VEGF/ KDR gene polymorphisms and RPL in Taiwanese Han women. (2) To explore the association between EG-VEGF, PKR1 and PKR2 gene polymorphisms and RPL in Taiwanese Han women. (3) To fine map the specific loci of PKR1 and PKR2 that influent susceptibility in recurrent miscarriage based on the result of specific aim 2. (4) To verify functional significance of specific variants by in vitro studies. In the results, we found (1) A functional SNP of KDR (Q472H) and haplotypes of VEGF and KDR are significantly associated with RPL in Taiwanese Han women. (2) Gene polymorphisms of PKR1 and PKR2 are significantly associated with RPL in Taiwanese Han women. EG-VEGF and its two receptor genes existed gene-gene interaction in RPL patients. (3) Based on results of specific aim 2, we found one each variat (I379V, V331M) in PKR1 and PKR2 could be the protective loci of RPL. (4) PKR1(I379V) and PKR2(V331M) altered the intracellular calcium influx and cell invasiveness. In conclusion, our study demonstrated that not only polymorphisms of KDR and PKR1/2 but also haplotypes of VEGF, KDR and PKR1/2 are associated with RPL. Among them, PKR1/2 variants may protect patients from recurrent abortion through altering calcium signaling and enhancing cell invasion ability which may facilitate embryo implantation and approaching sufficient oxygen and nutrient.
論文目次 Contents………………………………………………………………………………..….i
List of Figures …………………………………………………………………………...iv
List of Tables ………………………………………………………………………….…v
Abbreviation ……………………………………………………………………………vi
Abstract in Chinese……………………………………………………………………..1
I. Literature Review ………………………………………………………………4
1.1 Multifactorial recurrent pregnancy loss
1.2 Angiogenesis in human pregnancy
1.3 Gene polymorphisms as susceptibility factors in RPL
1.4 VEGF and KDR in early pregnancy
1.5 EG-VEGF and its two receptor genes (PKR1 and PKR2) in early pregnancy
1.6 Phenotypes of Pkr1/2 knockout mice
1.7 Human PKR2 mutations
1.8 Objectives of this work
II. Material and Method ……………………………………………………………9
2.1 Patients
2.2 Tag SNPs and functional SNPs selection
2.3 Genotyping
2.4 Statistic analysis for genetic association studies
2.5 Nucleotide sequence of PKR1 and PKR2 coding regions and PKRs variants identification.
2.6 RT-PCR for endogenous EG-VEGF, PKRs expressions in different cell lines
2.7 Plasmid construction, cell culture, transfection and protein expression
2.8 Intracellular calcium influx measurement
2.9 Cell proliferation
2.10 Cell invasion
2.11 Tube organization
III. Results ………………………………………………………………………….16
3.1 Characteristics of enrollers in genetic association study
3.2 KDR (Q472H) was associated with idiopathic RPL
3.3 VEGF and KDR haplotypes were associated with idiopathic RPL
3.4 PKR1, PKR2 polymorphisms and haplotypes were associated with idiopathic RPL
3.5 Gene-gene interaction existed in EG-VEGF system
3.6 PKR1 and PKR2 variants identified in RPL patients using nucleotide sequencing
3.7 PKR1 (I379V) and PKR2 (V331M) altered intracellular calcium signaling
3.8 No significant change of PKR1 (I379V) and PKR2 (V331M) in cell proliferation and tube organization
3.9 PKR1 (I379V) and PKR2 (V331M) increased cell invasiveness

IV. Discussion ……………………………………………………………………21
4.1 The role of VEGF in early pregnancy
4.2 The association of VEGF polymorphisms in RPL
4.3 The association of VEGF haplotypes in RPL
4.4 The effect and possible mechanism of KDR polymorphisms to human disease and early pregnancy
4.5 Spatio-temporal expression patterns of EG-VEGF and VEGF
4.6 EG-VEGF could be a uterine receptivity marker
4.7 Clinical association of human disorder with EG-VEGF and PKRs system
4.8 Trophoblast and decidual stromal cell invasion at the maternal-fetal interface
4.9 EG-VEGF and receptors involved in inflammatory and immune response in human pregnancy
4.10 G protein-coupled receptors (GPCRs) and cell invasion
4.11 PKR variants may play a role in preventing recurrent abortion
4.12 The potentials of tagging SNPs and multifactor dimensionality reduction (MDR) model in identification of disease-associated genes
V. Conclusion…………………………………………………………………….31
VI. References ……………………………………………………………………32
VII. Appendix ……………………………………………………………………...64
VIII. Publications…………………………………………………………………...82
IX. Curriculum vitae …………………………………………………………….85
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