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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/95787完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林劭品 | zh_TW |
| dc.contributor.advisor | Shau-Ping Lin | en |
| dc.contributor.author | 龔品睿 | zh_TW |
| dc.contributor.author | Pin-Jui Kung | en |
| dc.date.accessioned | 2024-09-16T16:25:54Z | - |
| dc.date.available | 2024-12-27 | - |
| dc.date.copyright | 2024-09-16 | - |
| dc.date.issued | 2024 | - |
| dc.date.submitted | 2024-08-01 | - |
| dc.identifier.citation | 1. Aalto AP, Pasquinelli AE. Small non-coding RNAs mount a silent revolution in gene expression. Curr Opin Cell Biol. 2012 Jun;24(3):333–40.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/95787 | - |
| dc.description.abstract | 與PIWI蛋白質結合長約24-34nt的小片段RNA(piRNA)主要表現在性腺，代表一群較少被研究的小片段非編碼RNA，其功能主要扮演後轉錄和轉錄基因靜默。它們除了在男性生殖扮演重要角色，近年來越來越多研究描述中樞神經系統中也存在類似piRNAs序列並可能具有功能，如影響突觸可塑性的潛力。本研究採用優化的生物資訊流程分析第二孕期流產人類胎兒睪丸的小片段RNA定序數據，樣本分別搜集於台灣和美國，並經過倫理批准。我們的研究發現，在人類胎兒睪丸中存在豐富piRNAs序列，而這些主要來自snoRNAs與轉譯相關基因。此外，顯著比例的生殖腺piRNAs可朔源或靶向通常在特定器官活躍之增強子序列，可能參與轉錄組調控甚或避免生殖細胞異常表現其他組織相關之基因。在生殖系統範籌之外，我們以自己建立並優化的生物資訊分析流程，重新探勘文獻中巴金森氏症逝者大腦組織的小RNA定序資料，亦解析出具有區分巴金森氏症患者與健康對照組個體的特定piRNA群組。令人振奮的是，在台灣巴金森氏症患者群體的血漿中，也發現了類似的趨勢，顯示此等piRNA在診斷上的應用價值。進一部探討這些巴金森氏症相關piRNAs對基因調控的影響，發現一群可能被piRNA調節的基因。我們在多個公開的轉錄組數據中觀察到高度一致的基因調控模式。對預測被抑制的piRNA標靶基因與神經退化的關聯性與可能機制提供有價值的見解。此外，從台灣巴金森氏症患者中血漿衍生的可能性piRNAs分析顯示出與巴金森氏症患者腦組織數據類似的趨勢，顯示這些與增強子相關的piRNAs可能貢獻於抑制目標調控區域，而這些調控區域多屬於典型增強子和超級增強子。面對區分巴金森氏症患者是否有認知障礙是具有挑戰的，尤其piRNAs於周邊血漿樣本中含量稀少更是目前難跨越的障礙。為了克服這一障礙，我們利用LC-MS/MS進行血漿中細胞外泌體之蛋白質譜定量分析，發現巴金森氏症併發認知障礙患者血漿外泌體有高TAOK1含量。經由ELISA平台驗證了血漿細胞外泌體中TAOK1表現可作為生物標誌物檢測巴金森氏症與阿茲海默症患者認知功能障礙的潛力。在神經細胞模型中，與tau病理相關的TAOK1不僅減少了細胞突出長度和細胞存活率，還降低了細胞中ATP產量，突顯了其病理學意義。我們的研究結果強調了piRNA和細胞外泌體蛋白生物標誌物在細胞命運調控、生存能力和平衡，突顯了它們在臨床診斷和治療中的潛力，並為發育和疾病的分子動態提供新見解。 | zh_TW |
| dc.description.abstract | PIWI-interacting RNAs (piRNAs), which are primarily expressed in gonads, represent a less explored class of small noncoding RNAs that are primarily expressed in gonads and play crucial roles in post-transcriptional and transcriptional gene silencing. Despite their known importance in male fertility, emerging evidence suggests a possible role for piRNAs in the central nervous system, potentially influencing synaptic plasticity. This study employed an optimized bioinformatic pipeline to analyze small RNA sequencing data from human fetal testes of second-trimester abortuses, with samples collected in Taiwan and the United States under ethical approval. Our investigation revealed a significant presence of putative piRNAs in human fetal testes, predominantly derived from snoRNAs and translation-related genes. Furthermore, these piRNAs appear to participate in transcriptome regulation and cell fate modulation through enhancer-associated interactions. Expanding beyond the germline scope, we reanalyzed putative piRNA sequences in postmortem brain tissues from Parkinson’s disease (PD) patients and identified specific putative piRNA populations that differentiate between PD patients and healthy controls. Similar trends were identified in plasma-derived putative piRNAs from Taiwanese PD patient cohorts, hinting at their diagnostic utility. Further exploration of gene regulation by these putative piRNAs revealed a significant frequency of genes being targeted. We observed a highly consistent pattern of gene regulation across multiple transcriptome datasets available in the public domain. The identification of piRNA-targeted genes predicted to be downregulated provided valuable insights into the cellular mechanisms underlying neurodegeneration. Moreover, analysis of plasma-derived putative piRNAs from a Taiwanese cohort of PD patients revealed trends analogous to those of PD brain datasets, suggesting that these enhancer-associated piRNAs likely contribute to the repression of target regulatory regions, such as those of typical enhancers and super enhancers. Addressing the challenges of differentiating impaired cognition in PD, the limited quantities of piRNAs pose a barrier to detection in peripheral samples. To overcome this obstacle, we conducted protein profiling of plasma extracellular vesicles (EVs), which revealed elevated levels of TAOK1 in PD patients with cognitive impairments. Validation through ELISA-based platforms confirmed the potential of plasma EV TAOK1 as a biomarker for detecting cognitive impairments in PD patients and Alzheimer’s disease (AD) patients. In neuronal cell line models, tauopathy-associated TAOK1 not only reduced neurite length and cell viability but also decreased ATP production when TAOK1 was overexpressed, highlighting its pathological significance. Collectively, our findings emphasize the role of piRNAs and EV protein biomarkers in cell fate modulation, viability, and homeostasis, highlighting their potential in clinical diagnostics and therapeutic treatments and providing new insights into the molecular dynamics of development and disease. | en |
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| dc.description.provenance | Made available in DSpace on 2024-09-16T16:25:54Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | Acknowledgement…………………………………………………………………... i
Abstract………………………………………………………………………….….. ii 中文摘要……………………………………………………………………………. iv Table of Contents………………………………………………………………..…... v List of Tables…………………………………………………………………..……. ix List of Figures…………………………………………………………………..…… xi Abbreviation…………………………………………………………………..…….. xiii Chapter One – Literature Review……………………...……………………..……... 1 1.1 The discovery and biogenesis of PIWI-interacting RNAs……………………..... 2 1.2 piRNA and human fetal gonads…………………………………………..……... 7 1.3 piRNA and neurodevelopmental and neurodegenerative disease………..……… 9 1.4 Development of biomarkers for cognitive impairment in PD patients…...…..…. 11 1.5 Schematic overview of this study.………...…………………..……………..…... 12 Chapter Two – PIWI-Interacting RNA Analysis in Human Fetal Gonads: Discoverying piRNA-Enhancer Associations in Cell Fate Control…………………. 14 2.1 Introduction…………………………………………………………………..….. 15 2.2 Materials and Methods……………….……………………………………..…… 17 2.2.1 Bioinformatic analysis of small RNA sequencing…………..……….…..…... 17 2.2.2 piRNA cluster prediction………………………………………………..…… 18 2.2.3 piRNA targets prediction……………………………………………..……… 18 2.3 Results……………………………………………………………………..…….. 18 2.3.1 Deciphering the dynamics of piRNA expression across human fetal development stages………………..……….………………..……….…..………….. 18 2.3.2 A significant portion of piRNAs in human fetal gonad originate from non-coding RNAs, suggesting a role in translational regulation during gonadal development………………..……….………………..……….……….………...….. 20 2.3.3 piRNA clusters target imprinted genes, such as KCNQ1OT1, and non-fetal related enhancers to regulate fetal gonad development…………………..……..…... 21 2.4 Discussion……………………………………………………………..……..….. 23 2.5 Conclusion…………………………………………………………….……..….. 28 2.6 Perspective…………………………………………………………….……..….. 29 2.6.1 Establishing 3’ end with 2’ O methylation enriched piRNA sequences.….… 29 2.6.2 Exploring the phenomenon observed in the human fetal gonad and its relevance across other species…………………………………………..…………. 29 2.6.3 Functional assays of putative piRNA target of interest……………………..... 30 2.7 Tables and Figures……………………………………………………………..... 32 2.7.1 Tables…………………………………………………………………….…... 32 2.7.2 Figures………………………………………………………………….……. 36 Chapter Three – Unveiling Distinctive piRNA Expression Profiles in Postmortem Brains and Plasma: Implications for Parkinson's Disease Diagnosis and Pathophysiology……..………..…..………..………………………...………..…… 40 3.1 Introduction………………………………………………………………….….. 41 3.2 Materials and Methods…………………………….……………………….….... 42 3.2.1 Sample preparation and library construction………………………………... 42 3.2.2 Bioinformatic analysis of small RNA sequencing…..…………………..…... 43 3.2.3 Prediction of piRNA-targeted genes and regulatory regions…………….….. 44 3.2.4 Statistical analysis……………………………………………………….…... 45 3.3 Results…………………………………………………………………….…….. 45 3.3.1 Identification and characterization of putative piRNAs from publicly available small RNA sequencing of PD brain datasets and plasma……...….……. 45 3.3.2 The discovery of brain-derived piRNA units in plasma offers potential diagnostic biomarkers for PD……...…………………………………………...…. 47 3.3.3 Exploring piRNA targets unveiled potential therapeutic targets in PD pathogenesis…………………..…………………….………………………….….. 48 3.3.4. Parallel characteristics of PD-associated putative piRNAs in peripheral circulation and the brain…………………………………………...…………..…... 50 3.4 Discussion…………………………………………………………………..…… 51 3.5 Conclusion……...…………………………………………………………..…… 57 3.6 Perspective………………...………………………………………………..…… 58 3.6.1 Validating biomarkers and strengthening confidence in piRNAs……….....… 58 3.6.2 Enhancing small RNA sequencing data volumn and establishing chromatin accessibility profiles in PD samples……………………………………………..… 59 3.6.3 Functional study on potential piRNA target candidates…………………..…. 61 3.6.4 Exploring the association between piRNA profiles and polymorphisms in PD patients…………………………………………………………………...……...… 62 3.7 Tables and Figures………………………………………………………..……... 64 3.7.1 Tables…………………………………………………………………..…….. 64 3.7.2 Figures……………………………………………………………….………. 68 Chapter Four – Elevated Plasma Levels of Extracellular Vesicle-associated TAOK1: A Diagnostic Marker for Cognitive Decline in Parkinson’s Disease Dementia and Alzheimer’s Disease..……………………………………………………………….. 75 4.1 Introduction…………………………………………………….……………..…. 76 4.2 Materials and Methods…………………………….………………………..…… 77 4.2.1 Sample collection………………………………………………………..…... 77 4.2.2 Isolating plasma-derived EV……………………………………………..….. 78 4.2.3 Mass spectrometric profiling…………………………………………..…….. 78 4.2.4 TAOK1 ELISA assay.……………………………………………….………. 79 4.2.5 Cell culture and treatment………………………………...……………..…… 80 4.2.6 Transfection…………………………………………………………..……… 80 4.2.7 Western blot…………………………………………………………..……… 81 4.2.8 Immunofluorescence staining……………………….………………..……… 82 4.2.9 Cell viability assay………………………………….………………...……… 82 4.2.10 ATP production assay……………………………...…………………..…… 82 4.2.11 Statistical analysis………………………………….…………………..…… 83 4.3 Results……………………………………………………………………..…….. 84 4.3.1 The significance of TAOK1 in LC-MS/MS and robust links to clinical cognitive assessment……………………...…………………………..……….…... 84 4.3.2 Successful ELISA validation of TAOK1 as a biomarker for monitoring cognitive impairment in PDD and AD…..….…………………………………..…. 86 4.3.3 The biological impact of TAOK1 on neurite shortening and ATP depletion in SH-SY5Y cells leading to neuronal cell death……………………………...…. 87 4.4 Discussion……………………………………………………………………… 89 4.5 Conclusion……………………………………..…………….………………… 95 4.6 Perspective……………………………………..………………………………. 95 4.6.1 Enhancing detection sensitivity of TAOK1 protein levels……………..…… 96 4.6.2 Investigating the functions of TAOK1……………………………..……….. 97 4.7 Tables and Figures…………………………………………………………….... 100 4.7.1 Tables……………………………………………………………………….. 100 4.7.2 Figures………………………………………………………………………. 102 Chapter Five – Extended Discussion, Perspective, and Conclusion Summary….….. 110 5.1 The importance of LINE-1 transposition in mammals…..……………..…..…... 111 5.2 Diagnostic and therapeutic potential of the piRNA…..……………………........ 113 5.3 Therapeutic potential of EVs in regenerative medicine…..……………………. 115 5.4 Perspective: Exploring the role of LINE-1 in genome dynamics and human health…….................................................................................................................. 117 5.5 Perspective: Advancing precision medicine in PD through piRNA targets…... 118 5.6 Perspective: The potential of TAOK1 in predicting cognitive decline and in serving as a drug target …………………………………………………………..... 119 5.7 Conclusion summary……...……………………………………………….…… 121 References…………………………………………………………………...……... 123 Appendix………………………………………………………………..………….. 142 Curriculum Vitae………………………………………………………..………….. 143 | - |
| dc.language.iso | en | - |
| dc.subject | 人類胎兒性腺 | zh_TW |
| dc.subject | 生物標記 | zh_TW |
| dc.subject | 外泌體 | zh_TW |
| dc.subject | 認知功能障礙 | zh_TW |
| dc.subject | 巴金森病 | zh_TW |
| dc.subject | piRNA | zh_TW |
| dc.subject | extracellular vesicle | en |
| dc.subject | cognitive impairment | en |
| dc.subject | Parkinson’s disease | en |
| dc.subject | human fetal gonad | en |
| dc.subject | PIWI-interacting RNA | en |
| dc.subject | biomarker | en |
| dc.title | 巴金森病與認知功能障礙患者之體內與循環分子生物標記： 從piRNA到細胞外泌體蛋白 | zh_TW |
| dc.title | Molecular Biomarkers in Situ and in Circulation in Patients with Parkinson’s Disease and Cognitive Impairment: from PIWI-interacting RNA to Extracellular Vesicle Protein | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 112-2 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.coadvisor | 吳瑞美 | zh_TW |
| dc.contributor.coadvisor | Ruey-Meei Wu | en |
| dc.contributor.oralexamcommittee | 朱雪萍;程吉安;王致恬;吳佳慶;何弘能;鄭珮琳 | zh_TW |
| dc.contributor.oralexamcommittee | Hsueh-Ping Chu;Chi-An Cheng;Chih-Tien Wang;Chia-Ching Wu;Hong-Nerng Ho;Pei-Lin Cheng | en |
| dc.subject.keyword | piRNA,人類胎兒性腺,巴金森病,認知功能障礙,外泌體,生物標記, | zh_TW |
| dc.subject.keyword | PIWI-interacting RNA,human fetal gonad,Parkinson’s disease,cognitive impairment,extracellular vesicle,biomarker, | en |
| dc.relation.page | 147 | - |
| dc.identifier.doi | 10.6342/NTU202402784 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2024-08-05 | - |
| dc.contributor.author-college | 生命科學院 | - |
| dc.contributor.author-dept | 基因體與系統生物學學位學程 | - |
| 顯示於系所單位： | 基因體與系統生物學學位學程 | |
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