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Title: | 探討Atg9的生理功能與分子調控機制 Characterization of Atg9 molecular regulation and physiological functions |
Authors: | Jung-Kun Wen 溫榮崑 |
Advisor: | 陳光超(Guang-Chao Chen) |
Keyword: | 細胞自噬,細胞自噬相關基因9, Autophagy,Atg9, |
Publication Year : | 2018 |
Degree: | 博士 |
Abstract: | 細胞自噬 (Autophagy)為細胞內高度保守的分解代謝機制,在各種壓力條件下,對於有機體存活,分化,發育,蛋白質質量控制,維持細胞穩態或病源體免疫反應來說,細胞自噬扮演重要的角色。而在調控細胞自噬反應的相關基因當中,細胞自噬相關基因9 (Atg9) 這一個具有多通道的穿膜蛋白,已往被認為是自噬體 (Autophagosomes)上膜的載體。根據之前的研究指出,Atg9能調節先天免疫反應以及氧化壓力條件下會調節JNK活性,這些研究都再再指出Atg9具有除了能夠調節細胞自噬外仍具有調控其他信息傳導路徑的功能。然而,Atg9在生物體發育過程中的分子調節及生理學上的重要性至今仍然不是非常的清楚。
在本研究中,我們透過Atg9的突變果蠅株,發現Atg9的缺乏會導致果蠅壽命縮短、活動力缺陷以及對於壓力的敏感性增加。除此之外,缺乏Atg9也造成果蠅腸道形態異常,腸道細胞明顯增大。有趣的是,我們發現抑制TOR信息傳導路徑可以回復Atg9突變果蠅的腸道細胞缺陷。進一步的我們找出Atg9透過與緊密連接蛋白(Patj)及TSC2的相互作用,進而調節TOR的活性。並且當缺乏Atg9時會導致TSC2蛋白質含量明顯降低。我們的研究結果揭示了Atg9和TOR信息傳導路徑在調控細胞生長和組織恆定性之間的拮抗關係。此外,我們透過遺傳操縱和系統性分析方法分析Atg9的突變果蠅株。我們發現Atg9的缺失也造成雌性果蠅具有生殖缺陷的現象。而在成蠅大腦中,Atg9高度表現在某些特定神經元區域。Atg9突變果蠅株所造成的生理現象以及在成蠅大腦神經元迴路上的表達模式,促使我們更進一步的想釐清Atg9在大腦神經元迴路中的功能以及如何調控全身性的代謝功能。 Autophagy is a highly conserved lysosome-mediated catabolic process, which can be activated by nutrient deprivation or other environment stresses. Autophagy is essential for organism survival, differentiation, development, protein quality control, maintaining cellular homeostasis and pathogens immune response. Atg9 has been shown to be the only integral membrane protein and reputed as a potential membrane carrier of autophagosomes. Moreover, Atg9 have been found to modulate innate immune response and oxidative stress mediated c-Jun N-terminal kinase (JNK) activation, indicating that Atg9 has multiple role in regulation of autophagy and others pathways. However, the molecular regulation and physiological functions of Atg9 still remain to be explored. In this thesis, we generated Atg9 null mutant flies and found that loss of Atg9 led to shortened lifespan, locomotor defects, and increased susceptibility to stress. Atg9 loss also resulted in aberrant adult midgut morphology with dramatically enlarged enterocytes. Interestingly, inhibiting the TOR signaling pathway rescued the midgut defects of the Atg9 mutants. In addition, Atg9 interacted with PALS1-associated tight junction protein (Patj), which associates with TSC2 to regulate TOR activity. Depletion of Atg9 caused a marked decrease in TSC2 levels. Our findings revealed an antagonistic relationship between Atg9 and TOR signaling in the regulation of cell growth and tissue homeostasis. Moreover, we discover that loss of Atg9 also causes female reproductive defects. In addition, Atg9 is highly expressed and enriched in some parts of fly brain. The Atg9 mutant phenotypes and the expression patterns, indicates that Atg9 may function in Drosophila adult brain neuron circuit and systemic metabolism. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/69607 |
DOI: | 10.6342/NTU201801070 |
Fulltext Rights: | 有償授權 |
Appears in Collections: | 基因體與系統生物學學位學程 |
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