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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 李立仁 | zh_TW |
dc.contributor.advisor | Li-Jen Lee | en |
dc.contributor.author | 林思妤 | zh_TW |
dc.contributor.author | Szu-Yu Lin | en |
dc.date.accessioned | 2023-10-03T17:47:27Z | - |
dc.date.available | 2023-11-10 | - |
dc.date.copyright | 2023-10-03 | - |
dc.date.issued | 2023 | - |
dc.date.submitted | 2023-08-09 | - |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/90825 | - |
dc.description.abstract | 泛自閉症類群障礙 (Autism spectrum disorder) 是一種病徵分布極廣並且在孩童時期就會發展起來的神經發育性疾病。根據衛生福利部疾病管制署的標準,患有泛自閉症類群障礙的病人會有語言溝通能力上的不足、社會互動上的障礙、有著較專一的興趣,並且會在他們身上發現重複性的行為的特徵。近期研究在一位患有泛自閉症類群障礙的台灣小男孩身上第八對染色體短臂23.2到末端的區域發現了一段長度2.4 Mb的微缺失(microdeletion),而這段缺失包含許多與神經精神疾病有相關的基因,其中,我們選擇了極靠近短臂末端的Fbxo25當作我們的目標基因。Fbxo25是SCF複合物 (含有Skp,Cullin,F-box) 中的E3泛素連接酶,參與泛素介導的蛋白降解作用。Fbxo25的功能主要是去辨認目標蛋白,使得SCF 複合物可以將目標蛋白接上泛素 (ubiqutin),而接上泛素的目標蛋白就能被送到蛋白酶體進行降解。我們利用Fbxo25基因敲除的模式小鼠來模擬8p23.2-pter病人的情形,以鑑定Fbxo25缺失的影響。Fbxo25突變小鼠在曠野實驗 (open field test)、高架十字迷宮 (elevated plus maze) 以及社交行為測試平台 (three-chamber social interaction test) 在活動力、焦慮程度以及社會互動上並未有明顯差異。而在居留者-入侵者實驗 (resident-intruder test) 中雖然並未發現Fbxo25突變小鼠更具有攻擊傾向,但是在與攻擊行為相關的腦區,尤其是杏仁核內側核 (medial nucleus of the amygdala) 以及下丘腦室旁核 (paraventricular nucleus of the hypothalamus),有更多表現c-fos的細胞。我們也利用新奇物識別實驗 (novel object recognition test) 以及巴恩斯迷宮 (Barnes maze test) 來分別測試Fbxo25突變小鼠的識別記憶 (recognition memory) 與空間學習記憶 (spatial learning memory),並發現Fbxo25突變小鼠有著較好的學習能力。由於Fbxo25高度表現在海馬迴,而且基因敲除小鼠有著更好的學習能力,我們接著去檢測與學習功能相關的腦區海馬迴的突觸蛋白表現量,尤其發現與記憶相關的突觸後麩胺酸(glutamate)受體GluN2A及mGluR5的蛋白表現量上升。根據Fbxo25降解蛋白的功能,我們比較了RNA定序及蛋白質體分析的結果,並找到了一些可能為Fbxo25所調控的蛋白。我們的研究鑑定了Fbxo25缺失小鼠的表現型,可做為第八對染色體短臂末端缺失症候群的動物模式。 | zh_TW |
dc.description.abstract | A microdeletion of 2.4Mb at the 8p23.2-pter region had been identified in a Taiwanese boy with autism spectrum disorder. Patients with 8p23.2-pter microdeletion were characterized by developmental delay, intellectual disability, microcephaly, autism spectrum disorder, attention-deficit/hyperactivity disorders, and mildly dysmorphic features. FBXO25 is located in this region and thus selected as a possible pathological candidate in 8p23.2-pter microdeletion syndrome. FBXO25 is a ubiquitin ligase included in a protein complex, SKP1-cullin-F-box, and is involved in protein degradation across the ubiquitin-proteasome system. We generated the Fbxo25 gene knockout mice to simulate the condition of 8p23.2-pter microdeletion. Fbxo25 mutant mice exhibited normal behavioral performances in the open field, elevated plus maze, and three-chamber social interaction tests. In the resident-intruder test, Fbxo25 mutants did not display aggressive behaviors, but more c-fos-positive nuclei in aggression-related regions including the medial nucleus of the amygdala and paraventricular nucleus of the hypothalamus were noticed in these mutants. We also determined the recognition memory and spatial learning in Fbxo25 mutants using novel object recognition test and Barnes maze test, respectively. Faster spatial learning was found in Fbxo25 KO mice. Since spatial learning is dependent on the function of the hippocampus in which Fbxo25 is highly expressed, we next examined the hippocampal protein levels. We found that GluN2A and mGluR5 were increased in the hippocampus of Fbxo25 KO mice. Considering the protein degradation function of Fbxo25, we compared the results of RNA sequencing and proteomic analyses, and several candidate substrates were identified. Together, the removal of Fbxo25 does not influence locomotor activities, short-term recognition memory, and social interaction but results in better spatial learning and aberrant protein expression in the hippocampus. Our study showed the impact of FBXO25 deficiency in mice which could be established as a novel model of 8p23.2-pter microdeletion. | en |
dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2023-10-03T17:47:27Z No. of bitstreams: 0 | en |
dc.description.provenance | Made available in DSpace on 2023-10-03T17:47:27Z (GMT). No. of bitstreams: 0 | en |
dc.description.tableofcontents | 中文摘要 iii
Abstract v List of figure and table ix Chapter 1. Introduction 1 Chapter 2. Material and Methods 4 2.1 Animals 4 2.2 Behavioral tests 5 Open field test 5 Elevated plus maze test 6 Marble burying test 6 Self-grooming test 7 Resident-intruder test 7 Three-chamber social test 8 Novel object recognition test 9 Barnes maze test 9 2.3 mRNA expression analysis 10 qPCR 11 RNA sequencing 12 2.4 Protein expression analysis 12 Proteomic analysis 12 Western blot assay 12 2.5 Histological examinations 14 Immunohistochemistry 14 Golgi stain, reconstruction, and morphology analyses of hippocampal DG granule cells 14 Analysis of dendritic spines 15 2.6 Statistical analysis 16 Chapter 3. Results 17 3.1 Verification in Fbxo25 mutant mice 17 3.2 Basic behaviors in Fbxo25 mutant mice 17 3.3 ASD-related behaviors in Fbxo25 mutants. 18 3.4 The hippocampal memory function in Fbxo25 mutant mice 19 3.5 The hippocampal protein expression in Fbxo25 mutant mice 20 3.6 Proteomic and transcriptome analyses in Fbxo25 mutant mice 23 3.7 Neuron morphology in Fbxo25 mutant mice 24 Chapter 4. Discussion 26 Figures and Tables 30 References 58 | - |
dc.language.iso | en | - |
dc.title | Fbxo25基因突變小鼠的表現型鑑定 | zh_TW |
dc.title | Phenotypic characterization of Fbxo25 mutant mice | en |
dc.type | Thesis | - |
dc.date.schoolyear | 111-2 | - |
dc.description.degree | 碩士 | - |
dc.contributor.oralexamcommittee | 高淑芬;王培育;鄭菡若;段立珩 | zh_TW |
dc.contributor.oralexamcommittee | Susan Shur-Fen Gau ;Pei-Yu Wang;Irene Han-Juo Cheng;Li-Heng Tuan | en |
dc.subject.keyword | 自閉症,動物模式,學習記憶,蛋白質降解, | zh_TW |
dc.subject.keyword | autism,animal model,learning and memory,protein degradation, | en |
dc.relation.page | 63 | - |
dc.identifier.doi | 10.6342/NTU202303663 | - |
dc.rights.note | 同意授權(全球公開) | - |
dc.date.accepted | 2023-08-09 | - |
dc.contributor.author-college | 醫學院 | - |
dc.contributor.author-dept | 解剖學暨細胞生物學研究所 | - |
顯示於系所單位: | 解剖學暨細胞生物學科所 |
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