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研究生:楊中維
研究生(外文):Yang, Chung Wei
論文名稱:以基因網絡分析探尋脊髓性肌肉萎縮症之潛在修飾基因並以小鼠模型評估他汀類藥物治療效果
論文名稱(外文):Transcriptomic analysis of potential modifier genes for investigating the treatment of spinal muscular atrophy and the efficacy of atorvastatin in a mouse model
指導教授:莊淳宇莊淳宇引用關係
指導教授(外文):Chuang,Chun Yu
口試委員:江啟勳鐘育志蔡力凱李小玲
口試日期:2017-01-24
學位類別:博士
校院名稱:國立清華大學
系所名稱:生醫工程與環境科學系
學門:工程學門
學類:生醫工程學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:英文
論文頁數:111
中文關鍵詞:脊髓性肌肉萎縮症微陣列分析BMP4atorvastatinSMA小鼠模型
外文關鍵詞:spinal muscular atrophymicroarray analysisBMP4atorvastatinSMA mouse model
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脊髓性肌肉萎縮症(spinal muscular atrophy; SMA)是一種遺傳性的神經肌肉疾病,主要成因與體內survival motor neuron (SMN)蛋白缺乏有關。SMA主要有四種不同嚴重度之疾病發展進程,其成因尚不明確,目前認為SMN2複製數目(copy number)為主要影響因子。本研究首先利用六個不同SMA疾病分型病人的血液樣本進行微陣列(microarray)前驅研究,探討SMA分型與SMN2複製數目對於疾病症狀嚴重度之影響,發現SMA分型對於神經相關功能基因之關聯性較SMN2複製數目高,顯示SMA疾病嚴重度可能有SMN2以外之基因來調控。因此,本研究進一步以ArrayExpress及Gene Expression Omnibus (GEO)基因資料庫中人類SMA組織樣本微陣列資料(microarray)進行分析,找出可能影響SMA嚴重度之基因,及調控其基因之藥物,探究對於SMA小鼠治療效果。
由基因資料庫收集39個不同分型的SMA患者組織資料進行整合基因分析,找出可能影響疾病嚴重度之目標基因。以weighted correlation network analysis (WGCNA)和gene network分析找出三條與嚴重度高度相關的調控路徑,分別為TNFα-BMP4-SERPINE1-GATA6 pathway (神經與心臟發育)、TNFα-PTGS2-BCL2 pathway (骨骼發育)及TNFα-IL6-CNTN1 pathway (神經系統發育),其中由receiver operating characteristic (ROC) curve analysis得知TNFα-BMP4-SERPINE1-GATA6 pathway具有預測SMA患病之AUC (area under curve)最高值0.8864,因此推論上游BMP4基因下調可能為影響SMA疾病關鍵之一。已有文獻指出BMP4可藉由一降膽固醇藥物atorvastatin提升,因此本研究以atorvastatin治療SMA小鼠,評估其療效。
SMA (Smn−/−SMN2+/−)新生小鼠每日腹腔注射atorvastatin (2.5、5和10 mg/kg/day) 治療8天後,結果顯示atorvastatin治療能延長SMA小鼠壽命,在體型、體重及運動協調性均有明顯改善,神經元退化及肌肉和心臟萎縮程度都有減緩情形,以及在脊髓、肌肉及心臟組織中均發現atorvastatin治療使Bmp4顯著上升。此外,SMA小鼠帶有之人類正常功能之SMN2基因表現並未因atorvastatin治療而提升,顯示atorvastatin療效並非透過增加SMN表現量。本研究發現atorvastatin 治療可能藉由提升Bmp4基因表現來改善SMA小鼠生理和行為能力之缺損,顯示BMP4為SMA治療之重要標的。
Spinal muscular atrophy (SMA) is an inherited neuromuscular disease caused by the deficiency of survival motor neuron (SMN) protein. There are majorly four types of SMA with different disease severities, and the specific mechanism of SMA is unclear. SMN2 copy number is considered as the major modifier in SMA. This study firstly conducted a pilot study in microarray analysis of six human blood samples to elucidate that SMA types had more influence than SMN2 copy number on SMA, and indicate the existence of other modifiers regulating for the phenotype of SMA. Therefore, this study further established an integrative transcriptomic analysis using human microarray tissue samples from microarray databases to identify the potential SMA target genes relevant to disease severity, and the efficacy of a candidate medicine worked on the targets was evaluated in a severe type of SMA mouse model.
The 39 human microarray datasets across different types of SMA tissues were used to construct an integrative transcriptomic analysis for recognizing novel target genes of SMA potentially regulating disease severity. This analysis was mainly conducted with the weighted correlation network analysis (WGCNA) along with Cytoscape network reconstruction to identify three regulation pathways associated with disease severity including TNFα-BMP4-SERPINE1-GATA6 (neural and cardiac development), TNFα-PTGS2-BCL2 (skeletal development), and TNFα-IL6-CNTN1 (nervous system development). The analysis of receiver operating characteristic (ROC) curve showed that TNFα-BMP4-SERPINE1-GATA6 pathway had the highest accuracy in SMA status (AUC = 0.8864), which meant that the down-regulation of up-stream gene BMP4 may be one of the key points in SMA pathogenesis. Previous studies have indicated that expression of BMP4 can be induced by a cholesterol lowering drug atorvastatin. Therefore, atorvastatin was chosen as the candidate medicine and evaluated its efficacy for SMA mice.
Daily intraperitoneally atorvastatin treatment (2.5, 5, and 10 mg/kg/day) prolonged the lifespan, increased body weight, and improved motor coordination in SMA mice (Smn−/−SMN2+/−). SMA mice receiving atorvastatin treatment for 8 days exhibited reduced motor neuron degeneration and muscle and cardiac atrophy as compared to control littermates. The expression of Bmp4 was significantly up-regulated but human SMN2 gene was not in spinal cord, muscular and heart tissues in SMA mice treated with atorvastatin. In conclusion, atorvastatin treatment modified biological and behavioral deficits in SMA mice potentially via up-regulation of Bmp4 expression, indicating the critical role of BMP4 in SMA treatment.
Table of contents I
List of tables IV
List of figures V
Abstract VIII
Chapter 1 Introduction 1
Chapter 2 Paper review 3
2.1 Spinal muscular atrophy………………………………………………………………………… ……3
2.2 SMA therapy………………………………………………………………………………………… …….4
2.3 SMA modifiers……………………………………………………………………………………… ……8
2.4 Microarray analysis of SMA study………………………………………………………… ……9
2.5 Weighted gene co-expression network analysis……………………………………… …11
2.6 Gene set enrichment analysis………………………………………………………………… ….12
Chapter 3 Study purpose 13
Chapter 4 Materials and methods 15
4.1 Recruitment and sample collection of human study subjects………………… ……15
4.2 RNA extraction in human blood samples and mouse tissues………………… ……15
4.3 Microarray analysis for human blood samples……………………………………… ……16
4.4 Transcriptomic data collection and preprocessing………………………………… ……17
4.5 WGCNA for identifying module genes in SMA……………………………………… …21
4.6 GSEA of ontological and functional characterization in SMA……………… ……21
4.7 Network analysis of chosen modules for selecting target genes……………… ….22
4.8 Animal preparation and drug treatment………………………………………………… ……22
4.9 Quantitative real-time PCR mRNA determination………………………………… …..25
4.10 ROC analysis in accuracy of target genes for SMA status………………… ……..27
4.11 Motor function tests for evaluating behavioral improvement in SMA mice…………………………………………………………………………………………………… …….27
4.12 Pathological determination for neurons and myocytes in tissues of SMA mice…………………………………………………………………………………………………… …….28
4.13 Retrograde tracing for assessing neural connections in tissues of SMA mice………………………………………………………………………………………………… ……….28
4.14 Statistical analysis…………………………………………………………………… ……………..29
Chapter 5 Results………………………………………………………………………………… …………………31
5.1 Pilot study for the regulation among different SMA status…………… …………..31
5.1.1 Identification of DEGs among SMA types……………………………… ……..31
5.1.2 Functional clusters of SMA types……………………………………………… ……33
5.1.3 Functional network analysis of SMA types………………………………… …..35
5.1.4 Potential neural hub genes of SMA types…………………………………… …..38
5.1.5 Gene network analysis of independent effects of SMA type and SMN2 copy number on disease progression…………………………………………… ….41
5.2 Integrative transcriptomic analysis of potential SMA target genes…… ………..47
5.2.1 Ontological network reconstruction of SMA……………………………… …..47
5.2.2 Target gene identification in SMA……………………………………………… ….51
5.2.3 Analysis of gene expression in SMA mice………………………………… ……52
5.2.4 Gene expression analysis in blood samples of SMA patients…………. .58
5.2.5 Molecular pathway exploration of SMA candidates……………………… ..59
5.3 Efficacy evaluation of target genes for medicine in a severe mouse model of SMA…………………………………………………………………………………………………… ……61
5.3.1 BMP4 signaling had specific accuracy to represent for SMA status. .61
5.3.2 Atorvastatin ameliorated the loss of motor neurons in spinal cord of SMA mice………………………………………………………………………………… ……64
5.3.3 Atorvastatin lessened muscle atrophy in SMA mice……………… ……….66
5.3.4 Atorvastatin improved the development of cardiac atrophy in SMA mice…………………………………………………………………………………………… ….67
5.3.5 Atorvastatin prolonged lifespan and improved motor strength of SMA mice………………………………………………………………………………………………. 69
5.3.6 Atorvastatin increased BMP4 and decreased TNFα expressions in SMA mice 73
Chapter 6 Discussion 76
6.1 Immune defects might be a critical factor in SMA 76
6.2 Potential roles of neuronal candidate genes from pilot human array analysis on SMA progression 77
6.3 SMA type is more relevant to disease progression than SMN2 copy number 78
6.4 Pathway of TNFα-Bmp4-Serpine1-Gata6 is critical for neuro-cardiac development in SMA mice 79
6.5 Pathway of TNFα-Ptgs2-Bcl2 regulates bone development in SMA mice 80
6.6 Pathway of TNFα-IL6-Cntn1 coordinates development of CNS system in SMA mice 81
6.7 Increase of BMP4 and reduction of TNFα improve motor neuron functions in neurodegenerations 82
6.8 Statins treatment improved neurological disorders in SMA mice 83
6.9 Atorvastatin up-regulates BMP4 and decreases TNFα to protect spinal cord neurons in SMA mice 85
6.10 Atorvastatin increases BMP4 and reduces TNFα to attenuate muscle atrophy in SMA mice 86
6.11 Atorvastatin increases BMP4 and reduces TNFα to improve cardiac musculature in SMA mice 87
6.12 Treatment dose of atorvastatin was concordant with clinical use 89
Chapter 7 Conclusion 92
Chapter 8 Future work 93
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