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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/82235完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳文彬(Wen-Pin Chen) | |
| dc.contributor.author | Chia-Hsuan Hsieh | en |
| dc.contributor.author | 謝佳軒 | zh_TW |
| dc.date.accessioned | 2022-11-25T06:34:07Z | - |
| dc.date.copyright | 2021-11-09 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-10-27 | |
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Santoso, M.R., et al., Exosomes From Induced Pluripotent Stem Cell-Derived Cardiomyocytes Promote Autophagy for Myocardial Repair. J Am Heart Assoc, 2020. 9(6): p. e014345. 41. Tikhomirov, R., et al., Exosomes: From Potential Culprits to New Therapeutic Promise in the Setting of Cardiac Fibrosis. Cells, 2020. 9(3). 42. Kolwicz, S.C., Jr., et al., Cardiac-specific deletion of acetyl CoA carboxylase 2 prevents metabolic remodeling during pressure-overload hypertrophy. Circ Res, 2012. 111(6): p. 728-38. 43. Ussher, J.R. and G.D. Lopaschuk, Targeting malonyl CoA inhibition of mitochondrial fatty acid uptake as an approach to treat cardiac ischemia/reperfusion. Basic Res Cardiol, 2009. 104(2): p. 203-10. 44. Teodoro, B.G., et al., Long-chain acyl-CoA synthetase 6 regulates lipid synthesis and mitochondrial oxidative capacity in human and rat skeletal muscle. J Physiol, 2017. 595(3): p. 677-693. 45. Williamson, D.L. and T.C. Rideout, Is ACSL6 at the crossroads of skeletal muscle lipid synthesis? J Physiol, 2017. 595(3): p. 619-620. 46. Brownsey, R.W., et al., Regulation of acetyl-CoA carboxylase. Biochem Soc Trans, 2006. 34(Pt 2): p. 223-7. 47. Wakil, S.J. and L.A. Abu-Elheiga, Fatty acid metabolism: target for metabolic syndrome. J Lipid Res, 2009. 50 Suppl(Suppl): p. S138-43. 48. Abu-Elheiga, L., et al., The subcellular localization of acetyl-CoA carboxylase 2. Proc Natl Acad Sci U S A, 2000. 97(4): p. 1444-9. 49. Takagi, H., et al., ACC2 Deletion Enhances IMCL Reduction Along With Acetyl-CoA Metabolism and Improves Insulin Sensitivity in Male Mice. Endocrinology, 2018. 159(8): p. 3007-3019. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/82235 | - |
| dc.description.abstract | "巴氏症候群（BTHS）是一種罕見遺傳性疾病，由位於X染色體上Xq28位置的Taffazin的編碼基因（TAZ）突變所引起。 Taffazin蛋白是一種酰基轉移酶，位於粒線體內膜和外膜之間的間隙中，對於心肌磷脂(Cardiolipin)的重塑(Remodeling)扮演重要的角色，以維持粒線體功能。此外，TAZ突變可能與左心室心肌致密化不全（LVNC）相關。 來自臺大醫院(NTUH)的巴氏症候群患者，即使採用最先進的藥物治療，也需採用新穎的治療策略來改善BTHS-LVNC的預後不良。 我們之前的研究發現，小鼠心臟Nkx2.5+細胞所分泌的外泌體(Exosome)可以顯著改善源自於LVNC患者的iPSC（LVNC-iPSC-hCM）人類心肌細胞之粒線體功能。 但是，我們仍不清楚若是來自健康的人類前驅細胞所分泌之外泌體(Exo)對於BTHS-LVNC-iPSC-hCM是否也能產生有效益的作用。而這項研究的目的為在早期分化階段之心肌細胞，也就是所謂人類中內胚層細胞分泌之外泌體（hMEC-Exo）是否具有治療效果，並揭示外泌體中有哪些重要的miRNAs以及其目標基因，釐清相關調控之訊息傳遞途徑，闡明是如何改善BTHS-LVNC-hCM之功能異常。在心肌細胞分化後的第20-70天期間，我們觀察到BTHS-LVNC-iPSC-hCM的表徵有（1）粒線體膜電位降低，（2）肌節排列不規則，（3）細胞大小增大，（4）細胞收縮功能降低，（5）受β-AR腎上腺受體促進劑（Iso）刺激的正性肌力收縮反應喪失，以及（6）評估粒線體功能的耗氧率（OCR）和細胞外產酸率（ECAR）二者皆降低。於第20-40天時給予hMEC-Exo（劑量為總Exosomal RNA含量100ng）的BTHS-LVNC-hCM組別中，發現了外泌體能保留肌節規則性排列和粒線體功能，並降低了凋亡細胞中VDAC1的表現量。 但是，如果治療時間於晚期才開始，也就是第50天後進行治療，發現hMEC-Exo對BTHS-LVNC-hCM的治療作用將幾乎消失。對外泌體中的miRNAs進行次世代定序，從來自三位健康人的外泌體中共同交集的41個miRs，發現其中某些miRs可能與調節脂肪酸生合成和粒線體代謝功能有關。 透過DIANA miR Path（v3.0）分析miRs的目標基因及其相關的信息傳遞途徑，發現miR-92a-3p, 205-5p, -125a-5p以及mir-302的家族成員等，皆可能參與調節脂肪酸代謝和線粒體功能。 需要進一步研究以驗證其相對應的目標基因和BTHS-LVNC-hCM中的訊息傳遞機制。 此外，根據先前研究顯示，TAZ缺陷會造成心臟粒線體中仰賴Coenzyme-A之氧化代謝作用異常，並透過增強蘋果酸-天門冬胺酸穿梭系統（Malate-aspartate shuttle）的補償機制來補足能量缺口，也為其他能被hMEC-Exo所調控的潛在治療目標提供了新的見解。總而言之，hMEC-Exo能改善BTHS-LVNC-hCM中心臟代謝功能的異常。 因此在未來，我們的工作正是找出具有療效性的外泌體之miRNAs，藉此全面性地恢復BTHS-LVNC-hCM粒線體功能。" | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-25T06:34:07Z (GMT). No. of bitstreams: 1 U0001-2710202115441000.pdf: 7045681 bytes, checksum: 6bae23568faa3900fae56cbcbe9b8a8c (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | "口試委員審定書 i 摘要 ii Abstract iv Index vii Abbreviation 1 Introduction 2 Objectives 5 Materials and Methods 6 Human induced pluripotent stem cell (hiPSC) culture 6 Differentiation of patient-specific human cardiomyocte (hCM) 6 JC-1 living cell staining 7 Wheat germ agglutinin (WGA) living cell staining 8 Immunocytochemistry (ICC) staining and confocal imaging 8 Cell shortening measurement 9 Mitochondria functional assay 9 Cell extraction and real-time qPCR validation 10 Exosome purification and isolation 11 Nanoparticle tracking analysis (NTA) 11 MicroRNA sequencing 12 Bioinformatics analysis 12 Short hairpin (sh)RNA lentivirus transduction for target genes knockdown 12 Statistical analysis 13 Results 14 The pedigree of BTHS-LVNC family and genetic mutation of human iPSC from BTHS-LVNC patient. 14 Apoptosis of mitochondrial in hiPSC-CMs derived from BTHS-LVNC patient. 15 Enlarged cell size was observed in BTHS-LVNC-hCMs on day 50. 16 Irregular sarcomere organization and impaired cell shortening of BTHS-LVNC-hCMs. 16 Impaired inotropic responses to β-adrenergic stimulation in BTHS-LVNC-hCMs. 17 Dysfunction of mitochondrial metabolism of hiPSC-CMs with TAZ mutation. 18 Transcriptional profile of metabolic related enzymes between healthy and BTHS hiPSC-CMs on day 20 versus day 70. 19 Pathological metabolic mechanism in TAZ mutant BTHS-LVNC cardiomyocytes. 20 Pre-treatment of exosome secreted from hMECs could improve mitochondrial function and sarcomere irregularity in BTHS-LVNC-hCMs. 22 Late treatment of exosome secreted from hMECs partially increased cell shortening and mitochondrial metabolic function in BTHS-LVNC-hCMs. 23 Potential exosomal miRNAs involved in fatty acid biosynthesis and metabolism pathway. 24 Cardiometabolic action and signaling mechanism of miR cocktail carried by healthy hiPSC-MEC-derived exosomes. 25 Knockdown of ACACA, ACACB and ACSL6 by lentiviral-mediated shRNA enhanced mitochondial membrane potential of BTHS-LVNC-hCMs. 25 Discussion 27 References 33 Figures 40 Figure 1. 40 Figure 2. 42 Figure 3. 48 Figure 4. 51 Figure 5. 55 Figure 6. 58 Figure 7. 60 Figure 8. 65 Figure 9. 67 Figure 10. 71 Figure 11. 73 Figure 12. 74 Supplementary Figures 79 Figure S1. 79 Figure S2. 80 Figure S3. 81 Figure S4. 84 Figure S5. 88 Figure S6. 90 Table 91 Table 1. List of primer pairs in the experiment. 91" | |
| dc.language.iso | zh-TW | |
| dc.subject | 微型核糖核酸 | zh_TW |
| dc.subject | TAZ | zh_TW |
| dc.subject | 巴氏症 | zh_TW |
| dc.subject | 左心室緻密化不全 | zh_TW |
| dc.subject | 人類誘導性多功能幹細胞 | zh_TW |
| dc.subject | 外泌體 | zh_TW |
| dc.subject | Barth syndrome | en |
| dc.subject | MicroRNA | en |
| dc.subject | Exosome | en |
| dc.subject | hiPSC-CM | en |
| dc.subject | LVNC | en |
| dc.subject | TAZ | en |
| dc.title | 人類中內胚層細胞分泌之外泌體能改善巴氏症伴隨左心室緻密化不全之心臟功能 | zh_TW |
| dc.title | Exosome secreted from human mesoendoderm cells could improve cardiac function of Barth syndrome with left ventricular non-compaction cardiomyopathy | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 林泰元(Hsin-Tsai Liu),楊鎧鍵(Chih-Yang Tseng) | |
| dc.subject.keyword | TAZ,巴氏症,左心室緻密化不全,人類誘導性多功能幹細胞,外泌體,微型核糖核酸, | zh_TW |
| dc.subject.keyword | TAZ,Barth syndrome,LVNC,hiPSC-CM,Exosome,MicroRNA, | en |
| dc.relation.page | 92 | |
| dc.identifier.doi | 10.6342/NTU202104345 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2021-10-27 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥理學研究所 | zh_TW |
| dc.date.embargo-lift | 2026-10-26 | - |
| 顯示於系所單位： | 藥理學科所 | |
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