臺灣博碩士論文加值系統

本論文共包含三個部分，以周邊血液微小核醣核酸(microRNAs, 簡稱miRNAs)生物標誌作為核心，探索其表現量與1) 精神分裂症表型、2) 生長發育與老化、以及3) 腦部功能與結構之關係。第一部份比較精神分裂症患者與健康對照組之周邊血液miRNAs表現量差異，以尋找精神分裂症潛在生物標記。首先，在學習組 (30位精神分裂症病人與30位性別年齡配對的健康對照組) 中，測量全基因體miRNAs表現量，共包含365個miRNAs。所選出的潛在生物標誌進一步在驗證組 (60位精神分裂症病人與30位健康對照組)中驗證其區分疾病狀態的能力。我們於2011找到七個潛在的miRNA生物標誌 (hsa-miR-34a, hsa-miR-449a, hsa-miR-564, hsa-miR-432, hsa-miR-548d, hsa-miR-572 和 hsa-miR-652) 可區別精神分裂症病人與正常人，在學習組，其ROC曲線下面積為95%，而驗證組，其曲線下面積亦達85%。這七個miRNAs當中，hsa-miR-34a在學習組與驗證組中表現量在精神分裂症患者與健康對照中皆有統計上顯著的差異。而這些微小核醣核酸並分別與病人的負性症狀、神經認知功能、事件關聯的電位波有顯著的相關。本研究顯示對於周邊血液之miRNAs表現偏差有潛力可作為精神分裂症生物標誌，但仍有多項挑戰性議題值得進一步探討與研究。第二部份欲瞭解產後嬰兒與成人之間miRNA的變化的情形，比較30位早產兒與60位成人的365個miRNA在周邊血液的表現圖譜。將近三分之一的miRNA被發現在早產兒與成人表現無差異，而另三分之一的miRNA在兩組表現量有顯著差異，剩下的三分之一則在兩組大部分的樣本中均沒有表現。基於miRNA在兩組表現的特性，將其分為五個類別。而從這五類別中選出7個miRNA在包含早產兒、兒童與成年的獨立樣本作驗證，有6個得到驗證。而比較五種類別miRNA的基因在染色體座落位置，有兩個區域被發現集中表現特定類型的miRNA，其中，隨年齡穩定表現的miRNA集中在14q32.31染色體位置，另外在成人中顯著表現量增加的miRNA則集中在9q22.21染色體位置。進一步，在成人組中，我們發現6個miRNA表現量在較老的成人比起較年輕的成人有顯著的減少。而我們選擇其中4個miRNA在驗證樣本也得到證實。最後，使用生物資訊方法進行功能性探索分析，結果顯示在嬰兒與成人之間表現量有顯著差異的miRNA，其共同參與的功能為免疫反應以及免疫相關疾病。此研究提供一個從嬰孩，成人到老年的周邊血液miRNA表現圖譜，歸類出隨年齡表現型態不同的miRNA與其可能的參與的生物功能。第三部分嘗試了解七個潛與精神分裂症相關的周邊血液miRNA的表現量 (hsa-miR-34a, hsa-miR-449a, hsa-miR-564, hsa-miR-432, hsa-miR-548d, hsa-miR-572 和 hsa-miR-652)與大腦皮質體積、厚度、以及表面積之間的相關性。研究包含35位精神分裂症病人與12位健康對照。我們分別在病人，以及健康對照樣本中，使用皮爾森相關性分析，探索每個miRNA與各腦區皮質結構之相關性。在病人組中，hsa-miR-449a與右腦後側扣帶迴體積 (posterior cingulate gyrus, r = 0.62, p = 0.0001)相關。而hsa-miR-572與hsa-miR-652分別與左腦後中前額葉皮層厚度 (caudal middle frontal cortex, r = -0.55,p = 0.0014) 以及左腦楔葉皮層厚度(cunues cortex, r = -0.55,p = 0.001) 相關。而在健康對照組中，只有hsa-miR-34a與左腦副海馬迴體積 (parahippocampal gyrus, r= -0.87, p = 0.0014)、和右腦眶部體積/表面積 (pars orbitals, r = -0.84 ~ -0.87, p <0.0006) 相關。值得注意的是，在精神分裂症患者中，大部分區域的灰質厚度以及血液miRNA表現量都隨著罹病年數的增加而下降。本研究指出某些miRNA表現量的變化可能與潛在的灰質結構異常有關，而且其與灰質厚度的相關性，在罹病年數較短的病人當中更為明顯。

This dissertation aims to evaluate the application of microRNAs (miRNAs) in the peripheral blood as biomarkers in predicting diagnosis of schizophrenia, human development and aging, and their association with cortical gray matter structures. It consists of three studies that included slightly different participants and different outcomes. Study I aimed to identify potential miRNA signature for schizophrenia by comparing genome-wide miRNA expression profiles in patients with schizophrenia vs. healthy controls. A genome-wide miRNA expression profiling was performed using a Taqman array of 365 human miRNAs in the peripheral blood mononuclear cells (PBMC) of a learning set of 30 cases and 30 controls. A seven-miRNA signature (hsa-miR-34a, hsa-miR-449a, hsa-miR-564, hsa-miR-432, hsa-miR-548d, hsa-miR-572 and hsa-miR-652) was derived from a supervised classification with internal cross-validation, with an area under the curve (AUC) of receiver operating characteristics of 93%. The putative signature was then validated in an independent testing set of 60 cases and 30 controls, with an AUC of 85%. These miRNAs were differentially correlated with patients’ negative symptoms, neurocognitive performance scores, and event-related potentials. The results indicated that the blood-based miRNA profiling is a feasible way to identify biomarkers for schizophrenia, and the seven-miRNA signature warrants further investigation. Study II aimed to investigate the changes in blood-based miRNA expression from preterm infants to adulthood. We compared 365 miRNA expression profiles in a screening set of preterm infants and adults. Approximately one-third of the miRNAs were constantly expressed from postnatal development to adulthood, another one-third were differentially expressed between preterm infants and adults, and the remaining one-third were not detectable in these two groups. Based on their expression in infants and adults, the miRNAs were categorized into five classes, and six of the seven miRNAs chosen from each class except one with age-constant expression were confirmed in a validation set containing infants, children, and adults. Furthermore, six miRNAs detectable in adults were down-regulated in older adults, and four chosen for individual quantification were verified in the validation set. Our results provide an overview on the regulation pattern of blood miRNAs throughout life and the possible biological functions performed by different classes of miRNAs. Study III aimed to investigate whether the expression levels of the seven PBMC-based schizophrenia-associated miRNAs were associated with gray matter volume, thickness, surface area, as well as subcortical volume in schizophrenia patients in a sample of 35 patients with schizophrenia and 12 healthy controls. Hsa-miR-449a showed moderate positive association with the volume of right posterior cingulate cortex in cases. Hsa-miR-572 and hsa-miR-652 showed moderate negative association with the thickness of left caudal middle frontal gyrus and left cuneus cortex. Whereas in healthy controls, only hsa-miR-34a was negatively associated with left parahimppocamal gyrus and right pars orbitalis in volume/surface area structures. The reduction of most regions of thickness structures as well as PBMC-miRNA expressions were correlated with increasing duration of illness in schizophrenia patients. These findings indicate that the miRNA expression alteration in PBMC may be related to the cortical structural changes that occur with disease progression in patients with schizophrenia.

中文摘要 I
Abstract V
Contents VII
List of tables VIII
List of figures X
Chapter 1 Overview 1
Chapter 2 Study I－MicroRNA expression aberration as potential peripheral blood biomarkers for schizophrenia 7
2.1 Introduction 7
2.2 Results 9
2.3 Discussion 12
2.4 Materials and methods 16
2.5 References 23
2.6 Tables and Figures 31
Chapter 3 Study II－Modulated expression of human peripheral blood microRNAs from infancy to adulthood and its role in aging 52
3.1 Introduction 52
3.2 Results 52
3.3 Discussion 59
3.4 Materials and methods 65
3.5 References 70
3.6 Tables and Figures 75
Chapter 4 Study III－Association between miRNA expressions of peripheral blood mononuclear leukocytes and cortical gray matter structures in patients with schizophrenia and health controls 120
4.1 Introduction 120
4.2 Results 123
4.3 Discussion 125
4.4 Material and methods 130
4.5 References 134
4.6 Tables and Figures 144
Chapter 5 Conclusion and Implication 173
Appendix: Other publications by Chi-Yu Lai 176

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Study II
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