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系統識別號 U0026-2707201111562600
論文名稱(中文) 探討發炎基因多型性在發炎反應異常的腦性麻痺學齡早產兒中所扮演的角色
論文名稱(英文) The roles of polymorphisms in inflammatory genes of preterm, cerebral palsy children with dysregulated inflammatory responses
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 99
學期 2
出版年 100
研究生(中文) 林長儀
研究生(英文) Chang-Yi Lin
學號 s5893153
學位類別 博士
語文別 英文
論文頁數 100頁
口試委員 指導教授-黃朝慶
召集委員-張明熙
口試委員-呂政展
口試委員-劉校生
口試委員-張瑛玿
口試委員-薛佑玲
中文關鍵字 早產兒  腦性麻痺  基因多型性 
英文關鍵字 preterm  cerebral palsy  genetic polymorphism 
學科別分類
中文摘要 早產兒若在出生前後有發炎的情形會增加罹患大腦深部白質軟化症的機會並引起腦性麻痺的徵狀。而本研究首先想了解罹患大腦深部白質軟化症所引起的腦性麻庳早產兒是否在學齡時免疫反應會有所不同。我們首先收集32個罹患腦性麻庳的早產兒(7.2±3.6歲)以及32個正常對照組的早產兒(6.2±2.2歲),並測量血漿中和周邊單核球細胞在多酯醣(lipopolysaccharide; LPS)刺激後所產生的腫瘤壞死因子(tumor necrosis factor-alpha; TNF-),以及周邊單核球細胞的發炎基因表現。我們發現罹患腦性麻痺早產兒其血漿(p < 0.001),周邊單核球在LPS刺激後不僅所釋放的TNF- (p=0.003)比正常早產兒的都來的高,而且其細胞內的TNF-含量也相對比正常對照組來的高。我們也發現罹患腦性麻痺早產兒其體內單核球細胞的發炎基因mRNA表現比正常對照組來的高,其中包括有:Toll-like receptor 4 (TLR-4) (P = 0.0023), TNF- (P = 0.0016), transforming growth factor-β activated kinase 1 (P = 0.038), IB kinase- (P = 0.029), 和 c-Jun N-terminal kinase (P = 0.045),其中TLR4的表現與周邊單核球細胞在受到LPS刺激後所釋放TNF-含量成正比(Spearman rank correlation = 0.38, P = 0.03)。
然而,對於為何腦性麻痺早產兒其發炎反應會有所不同目前仍不清楚。有許多的研究指出TNFA基因上的對偶基因(LTA+250, TNFA-1031, TNFA-863, TNFA-857, TNFA-806, TNFA-308, 和 TNFA-238)與許多發炎相關的疾病有關。因此,我們接下來想了解是否基因的多型性會影響發炎程度的不同。我們找來了102個罹患腦性麻庳的早產兒(5±3歲)以及102個正常對照組的早產兒(4±2歲)並偵測其發炎基因上的多型性。結果發現,在TNFA-1031C (rs1799964) 基因型與發生由大腦深部白質軟化症所引起的腦性痲痺有關(odds ratio (OR)=2 for C carrier; p=0.03)。我們也發現帶有TNFA-1031C的早產兒其周邊單核球在經過LPS刺激後會產生較高的的TNF-,且帶有TNFA-1031C的報告基因也有較高的表現。Electrophoretic mobility shift assays的實驗也顯示轉錄因子對於TNFA-1031C有較高的親和力,這也表示TNFA-1031C會使TNFA有較高的表現,Super shift assay以及Chromatin immunoprecipitation assay更顯示出PU.1 (spi-1)會結合在TNFA-1031的位子上並且對於TNFA-1031C有高的親和力,因此我們証實了TNFA上的多型性可能會改變罹患腦性痲痺早產兒的發炎反應。
綜合以上結果,我們發現TNFA-1031基因多型性會影響TNFA基因的表現,而且與腦性麻痺早產兒的發炎反應異常有關。然而除了基因以外,表基因(epigenetic effect)是否也參與發炎反應異常則需進一步的研究。
英文摘要 Perinatal inflammatory responses contribute to periventricular leukomalacia (PVL) and cerebral palsy (CP) in preterm infants. Here, we first examined whether the preterm children with CP had altered inflammatory responses when school-aged. 32 preterm children with PVL-induced CP [mean (±SD) age, 7.2±3.6 years] and 32 control preterm children with normal neurodevelopment (6.2±2.2 years) and matched for gestational age were recruited. We measured tumor necrosis factor (TNF)- levels in the plasma and the supernatants of peripheral blood mononuclear cells (PBMCs) with and without lipopolysaccharide (LPS) stimulation, and proinflammatory genes expression in the PBMCs. TNF- expression was significantly higher in the plasma (P < 0.001) and supernatants of LPS-stimulated PBMCs (P = 0.003) in CP group than in control group. After LPS stimulation, the intracellular TNF- level in the PBMCs significantly downregulated in control group (P = 0.016) and significantly upregulated in CP group (P = 0.01). The CP group also had, in their non-stimulated PBMCs, significantly higher mRNA levels of inflammatory molecules: Toll-like receptor 4 (TLR-4) (P = 0.0023), TNF- (P = 0.0016), transforming growth factor-β activated kinase 1 (P = 0.038), IB kinase- (P = 0.029), and c-Jun N-terminal kinase (P = 0.045). The TLR-4 mRNA levels in the PBMCs were highly correlated with TNF- levels in LPS-stimulated PBMCs (Spearman rank correlation = 0.38, P = 0.03).
However, the underlying causes of altered inflammatory responses in the preterm children with PVL injury-induced CP remains unknown. We next examined whether genetic effects had contributed to altered inflammatory responses. Some alleles of TNFA (LTA+250, TNFA-1031, TNFA-863, TNFA-857, TNFA-806, TNFA-308, and TNFA-238) have been associated with susceptibility and/or severity of many diseases characterized by inflammation and/or immune system. One hundred and two preterm children with PVL-induced CP [mean (±SD) age, 5±3 years] and 102 control preterm children with normal neurodevelopment (4±2 years) and matched for gestational age were recruited. We found that TNFA-1031 T-to-C variant (rs1799964) in the promoter associated with increased risk of PVL-induced CP (odds ratio (OR) =1.98 for C carrier; p<0.05). We also observed higher TNF- levels in the presence of the C allele in the supernatants of PBMCs after LPS stimulation (p<0.05). The -1031C-allele-promoter construct exhibited increased luciferase reporter gene expression. Electrophoretic mobility shift assays showed that the -1031C allele enhanced the binding affinity of some transcription factor, accounting for higher TNFA promoter activity. Supershift assays and chromatin immunoprecipitation assay further revealed that the protein of interest was PU.1 (Spi-1) and PU.1 preferred TNFA-1031C to TNFA-1031T. These data indicated that genetic variations in TNFA promoter may modify inflammatory responses in the preterm children with PVL injury-induced CP.
Taken together, we found that TNFA-1031T/C polymorphism could modulate TNFA expression and involve in dysregulated inflammatory responses in PVL-induced CP preterm children. However, besides genetic effect, whether epigenetic effect would also involve in dysregulated inflammatory responses is still needed to be further investigated.
論文目次 Content
中文摘要………………………………………………………………………………2
Abstract…………………………………………………………………………..……4
Acknowledgement…………………………………………………………..……….7
Content…………………………………………………………………………..…….9
Table and Figure lists...……………………………………………..………………12
Introduction…………………………………………………………………………14
Periventricular leukomalacia and inflammation.……………………………14
Early-life injury and persistent inflammatory responses……………….…….17
Genetic variations and PVL susceptibility………………………...…………18
PU.1 (spi-1) and TNFA promoter activity……………………..……………..22
Hypothesis and aims………………....……………………………………………….23
Materials and methods……………………………………………………………….26
Subjects…………………………………………...………………………….26
Magnetic Resonance Imaging………………………….…………………….27
Isolating Peripheral Blood Mononuclear Cells……………..………………..28
Flow Cytometry………………………………………………...…………….29
Microarray Experiments and Real-Time Polymerase Chain Reaction……....29
SNP selection and genotyping…………………………………………..……31
Construction of promoter-reporter plasmids…………………………………33
Transfection and luciferase reporter assays………………………….……….33
Electrophoresis mobility shift assay (EMSA)………………………..………34
Chromatin immunoprecipitation Analysis (ChIP)…………………...………35
Lentiviral Vector Transduction……………………………………..………..36
Statistics…………………………………………………………...…………36
Results…………………………………………………………………………….….38
Clinical Characteristics and Outcome in dysregulated inflammatory responses study……………………………………………..……………………..…….38
Plasma Levels of TNF- and IL-6………………………………...………38
TNF- Expression in LPS-Stimulated PBMCs……………….………….….39
Inflammatory Signaling Molecular Expression in PBMCs…………………41
Clinical Characteristics and Outcome in genetic polymorphisms study……..42
Genotyping and Risk of Periventricular Leukomalacia in Preterm Children...44
Functional Significance of the TNFA-1031 polymorphism on TNFA Expressive Activity…………………………………………………………..45
TNFA-1031 Variant Increases Transcription Factor Affinity to Promoter…..47
PU.1 is Identified as the Target Transcription Factor that Exhibits Allele- specific Binding to Location of TNFA-1031T/C polymorphism…………….48
Conclusion and Discussion………………………………..………………………..51
References……………………………………………………………………………62
Tables……………………………………………………………………..………….73
Table 1………………………………………………………………………..73
Table 2……………………………………………………………………..…75
Table 3……………………………………………………………………..…78
Table 4………………………………………………………………………..80
Table 5…………………………………………………………………….….83
Table 6…………………………………………………………………….….84
Figures and Figure legends…………………………………………………………..85
Figure 1………………………...….…………………………….……………..85
Figure 2………………………...…..…………………………………………..86
Figure 3…………………………...……………………………………………88
Figure 4…………………………...……………………………………………90
Figure 5…………………….…..………………………………………………92
Figure 6……………………………………………………………………...…93
Figure 7………………………………………………………………..….........94
Figure 8……………………………………………………………………...…95
Figure 9…………………………………………………………………….......97
Figure 10……………………………………………………………………….98
Figure 11…………………………………………….…………………………99
Publications………………………………………………………..………………..100
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