探究粒線體衍胜肽對粒線體功能障礙的細胞保護作用

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題名:	探究粒線體衍胜肽對粒線體功能障礙的細胞保護作用 Investigating the Cytoprotective Effects of Mitochondrial-Derived Peptides on Mitochondrial Dysfunction
作者:	朱珮玲 CHU, PEI-LING
貢獻者:	醫學檢驗暨生物技術學系碩士班高淑慧
關鍵詞:	粒線體衍胜肽;Pearson 症候群;人類素;粒線體DNA突變 mitochondria-derived peptides;Pearson syndrome;humanin;mtDNA mutation
日期:	2021-07-14
上傳時間:	2022-03-28 19:30:34 (UTC+8)
摘要:	Pearson 症候群為一種罕見的粒線體疾病，致病原因主要為粒線體 DNA 大片段缺失，大多數認為在胚胎發育早期偶發性形成粒線體突變，只有少部分認為與遺傳相關。先前實驗室已為 Pearson 氏患者母親之體外受精胚胎進行植入前基因檢測，發現其具有與患者相同之 4237 鹼基對刪除的粒線體突變型，認為於患有疾病高風險之家族中，胚胎著床前基因診斷是必要的，所以本次實驗利用 PCR、 Nested PCR 以及 DNA 定序等實驗，於病患母親第二次體外受精之胚胎進行針對 Pearson 疾病的突變型粒線體 DNA 檢測，並且發現與先前患者一樣之 4237 bp 大片段缺失突變型，但於病患父母之體細胞中 (毛囊細胞、頰黏膜細胞及周邊血液細胞) 沒有發現相同之突變，疾病之傳播模式似乎與遺傳具有相關。另一方面，透過體外培養患者初代之皮膚纖維母細胞 (Patient fibroblasts, PF )，研究粒線體衍生肽—人類素 (humanin)，對於粒線體異質體之影響。人類素可以可經由細胞內和細胞外活化細胞保護路徑有效介導粒線體至細胞核逆行訊息來對應嚴重的粒線體損傷和細胞壓力。在本研究中，透過病患纖維母細胞株作為分析粒線體衍胜肽人類素對應粒線體壓力時的分子調控機制。結果發現人類素顯著增加了病患纖維母細胞之細胞內 ATP 水平，並且減少因粒線體損害所導致的粒線體DNA拷貝數代償性增加，以及降低粒線體DNA突變量。本研究目標釐清粒線體衍胜肽humanin分子作用機制，並希望作為粒線體損害疾病開發未來治療的方法。 Pearson syndrome is a rare mitochondrial disease. The main cause of the disease is the large scale deletion of mitochondrial DNA (mtDNA). Most of people believe that mitochondrial mutations were generated sporadically in early embryonic development. Only a few consider it is transmitted by maternal inheritance. Previously, we had performed preimplantation genetic diagnosis (PGD) for the in vitro fertilized (IVF) embryos from proband’s mother, and found that they had the same 4237 bp deleted mtDNA as the patient. Using PCR, Nested PCR and DNA sequencing, we further tested the mutant type of mtDNA in connection with Pearson disease on the second IVF embryos from patient’s mother. We found the identical 4237 bp deletion of mtDNA in all the harvested IVF embryos which did not be detected in the somatic cells (hair follicle cells, buccal cells and peripheral blood cells) of proband’s parents. Mitochondria-derived peptides (MDPs) are small peptides encoded by mitochondrial DNA (mtDNA), serve as signals for organism cytoprotection and energy regulation. In the present study, we aimed to identify the effect of mitochondrial-derived peptide (MDPs), humanin, on improving mitochondrial function and reducing the mitochondrial DNA mutation loads. By culturing the primary skin fibroblasts from the patient with Pearson’s syndrome in vitro. Humanin is a potent mediator of mitochondrial retrograde signaling response to pathogenic mitochondrial damage and cellular stress in vivo and in vitro. In the study, we characterized the effects of humanin response to the mitochondrial stress in PF. We found that humanin improves ATP production and mitochondrial bioenergetics, ameliorates the commendatory extension of mtDNA copy number, and reduced the mtDNA mutation load in the PF. A better understanding of molecular mechanisms of humanin provides new therapeutic targets for mitochondrial-damaged related diseases.
描述:	碩士指導教授：高淑慧委員：張壯榮委員：郭雲鼎
資料類型:	thesis
顯示於類別:	[醫學檢驗暨生物技術學系所] 博碩士論文

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