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題名 Vha16-1對果蠅腸道功能和壽命之調控
Vha16-1 regulates intestinal function and lifespan in Drosophila melanogaster作者 宋祐陞 貢獻者 王培育
宋祐陞關鍵詞 突變生成
壽命
肥胖
腸道酸化
mutagenesis
lifespan
obesity
gut acidification日期 2011 上傳時間 30-Oct-2012 15:22:11 (UTC+8) 摘要 突變生成(mutagenesis)的方式有許多種，其中insertional mutagenesis為果蠅上常使用建立突變株的方式，本篇論文利用p[GawB]隨機插入果蠅genome中產生大量突變株，並篩選出會影響壽命的突變果蠅M2。進一步的實驗發現M2果蠅為Vha16-1基因的突變，並造成其mRNA表現量的下降，且在低卡路里(5% yeast、5% dextrose)與高卡路里(15% yeast、15% dextrose)的環境下homozygous mutant果蠅皆有減少平均壽命的現象。 Vha16-1所表現的蛋白為Vacuolar-type H+-ATPase (V-ATPase)上的subunit c，V-ATPase主要的功能為藉由消耗ATP來運送氫離子，並可調節胞器或胞外腔室的酸鹼平衡。V-ATPase主要表現在果蠅腸道的copper cell上，此細胞的功能類似於哺乳動物的胃壁細胞(parietal cells)，與胃酸的分泌有關，我們發現M2 homozygous mutant果蠅因Vha16-1基因的缺失而有減少腸道酸化的情形發生，符合我們觀察到其在腸道上的表現。此一現象亦在另一株突變果蠅Vha16-1EP2372上加以證實。先前研究顯示果蠅腸道酸鹼平衡的破壞會影響到對養分的吸收，而Vha16-1的缺失亦導致M2果蠅體重與三酸甘油酯的上升，並增加對飢餓的耐受性，而這些代謝上的變化並不會改變M2果蠅對食物的攝取量或者生育能力。綜合這些實驗結果，我們推測Vha16-1基因的缺失會改變腸道功能，並影響果蠅體內代謝的狀態，表現出類似肥胖(obesity)的性狀，而終導致平均壽命的縮短。
Mutagenesis can be induced by many ways and one of the most common approaches used in Drosophila is insertional mutagenesis. In this study, we screened pGawB insertion lines and identified M2 as a novel mutant with affected lifespan. The mutant allele of M2 carried a pGawB inseration at the 5’ end of the Vha16-1 gene, which caused a reduced Vha16-1 mRNA expression level and a shorten lifespan in homozygous mutants under both low calorie (5% yeast and 5% dextrose) and high calorie (15% yeast and 15% dextrose) foods. Vha16-1 encodes the c subunit of the Vacuolar-type H+-ATPase (V-ATPase) which is known to regulate pH homeostasis by pumping protons across organelle and plasma membranes. V-ATPase is highly expressed by the Copper cells which are located at the Drosophila middle midgut and functionally similar to the gastric acid producing parietal cells in mammals. Along the same line, we found that Vha16-1 pGawB drives GFP reporter was observed along the Drosophila gastrointestinal tract. M2 as well as the other Vha16-1 hypomorphic mutant line, EP2372, also showed reduced midgut acidification. This disrupted pH homeostasis in the Drosophila midgut region may be associated with increased body weight, triglyceride, and starvation resistance that observed in M2 mutants. The feeding behavior and reproductive function, however, were not affected in M2 mutant flies. In summary, our data suggested Vha16-1 deficits may alter normal intestinal function or internal metabolic status that ultimately induces obesity phenotypes with reduced lifespan.參考文獻 Allan AK, Du J, Davies SA, Dow JA (2005) Genome-wide survey of V-ATPase genes in Drosophila reveals a conserved renal phenotype for lethal alleles. Physiol Genomics 22:128-138. Allman E, Johnson D, Nehrke K (2009) Loss of the apical V-ATPase a-subunit VHA-6 prevents acidification of the intestinal lumen during a rhythmic behavior in C. elegans. Am J Physiol Cell Physiol 297:C1071-1081. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337-342. Beyenbach KW, Wieczorek H (2006) The V-type H+ ATPase: molecular structure and function, physiological roles and regulation. J Exp Biol 209:577-589. Birse RT, Choi J, Reardon K, Rodriguez J, Graham S, Diop S, Ocorr K, Bodmer R, Oldham S (2010) High-fat-diet-induced obesity and heart dysfunction are regulated by the TOR pathway in Drosophila. Cell Metab 12:533-544. 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國立政治大學
神經科學研究所
98754008
100資料來源 http://thesis.lib.nccu.edu.tw/record/#G0098754008 資料類型 thesis dc.contributor.advisor 王培育 zh_TW dc.contributor.author (Authors) 宋祐陞 zh_TW dc.creator (作者) 宋祐陞 zh_TW dc.date (日期) 2011 en_US dc.date.accessioned 30-Oct-2012 15:22:11 (UTC+8) - dc.date.available 30-Oct-2012 15:22:11 (UTC+8) - dc.date.issued (上傳時間) 30-Oct-2012 15:22:11 (UTC+8) - dc.identifier (Other Identifiers) G0098754008 en_US dc.identifier.uri (URI) http://nccur.lib.nccu.edu.tw/handle/140.119/55037 - dc.description (描述) 碩士 zh_TW dc.description (描述) 國立政治大學 zh_TW dc.description (描述) 神經科學研究所 zh_TW dc.description (描述) 98754008 zh_TW dc.description (描述) 100 zh_TW dc.description.abstract (摘要) 突變生成(mutagenesis)的方式有許多種，其中insertional mutagenesis為果蠅上常使用建立突變株的方式，本篇論文利用p[GawB]隨機插入果蠅genome中產生大量突變株，並篩選出會影響壽命的突變果蠅M2。進一步的實驗發現M2果蠅為Vha16-1基因的突變，並造成其mRNA表現量的下降，且在低卡路里(5% yeast、5% dextrose)與高卡路里(15% yeast、15% dextrose)的環境下homozygous mutant果蠅皆有減少平均壽命的現象。 Vha16-1所表現的蛋白為Vacuolar-type H+-ATPase (V-ATPase)上的subunit c，V-ATPase主要的功能為藉由消耗ATP來運送氫離子，並可調節胞器或胞外腔室的酸鹼平衡。V-ATPase主要表現在果蠅腸道的copper cell上，此細胞的功能類似於哺乳動物的胃壁細胞(parietal cells)，與胃酸的分泌有關，我們發現M2 homozygous mutant果蠅因Vha16-1基因的缺失而有減少腸道酸化的情形發生，符合我們觀察到其在腸道上的表現。此一現象亦在另一株突變果蠅Vha16-1EP2372上加以證實。先前研究顯示果蠅腸道酸鹼平衡的破壞會影響到對養分的吸收，而Vha16-1的缺失亦導致M2果蠅體重與三酸甘油酯的上升，並增加對飢餓的耐受性，而這些代謝上的變化並不會改變M2果蠅對食物的攝取量或者生育能力。綜合這些實驗結果，我們推測Vha16-1基因的缺失會改變腸道功能，並影響果蠅體內代謝的狀態，表現出類似肥胖(obesity)的性狀，而終導致平均壽命的縮短。 zh_TW dc.description.abstract (摘要) Mutagenesis can be induced by many ways and one of the most common approaches used in Drosophila is insertional mutagenesis. In this study, we screened pGawB insertion lines and identified M2 as a novel mutant with affected lifespan. The mutant allele of M2 carried a pGawB inseration at the 5’ end of the Vha16-1 gene, which caused a reduced Vha16-1 mRNA expression level and a shorten lifespan in homozygous mutants under both low calorie (5% yeast and 5% dextrose) and high calorie (15% yeast and 15% dextrose) foods. Vha16-1 encodes the c subunit of the Vacuolar-type H+-ATPase (V-ATPase) which is known to regulate pH homeostasis by pumping protons across organelle and plasma membranes. V-ATPase is highly expressed by the Copper cells which are located at the Drosophila middle midgut and functionally similar to the gastric acid producing parietal cells in mammals. Along the same line, we found that Vha16-1 pGawB drives GFP reporter was observed along the Drosophila gastrointestinal tract. M2 as well as the other Vha16-1 hypomorphic mutant line, EP2372, also showed reduced midgut acidification. This disrupted pH homeostasis in the Drosophila midgut region may be associated with increased body weight, triglyceride, and starvation resistance that observed in M2 mutants. The feeding behavior and reproductive function, however, were not affected in M2 mutant flies. In summary, our data suggested Vha16-1 deficits may alter normal intestinal function or internal metabolic status that ultimately induces obesity phenotypes with reduced lifespan. en_US dc.description.tableofcontents 謝誌 I 中文摘要 III Abstract IV 目錄 V 表次 VIII 圖次 IX 縮寫對照表 X 第一章 緒論 1 第一節、 突變生成(mutagenesis) 1 一、 Ethyl methanesulfonate (EMS) 1 二、 Radiation 1 三、 Insertional mutagenesis 1 第二節、 Vacuolar-type H+-ATPase 2 第三節、 果蠅腸道及其功能 4 第四節、 代謝與老化之關連 5 第五節、 本論文研究目的 6 第二章 實驗材料與方法 7 第一節、果蠅種類及來源 7 第二節、實驗藥品 7 第三節、食物培養基配方 8 第四節、果蠅飼養與存活率分析試驗 8 第五節、Mutagenesis 9 第六節、Inverse PCR 11 一、 Genomic DNA extraction 11 二、 Restriction enzyme digestion 11 三、 DNA Ligation 11 四、 DNA purification 11 五、 DNA amplification 12 六、 Genotyping 12 第七節、及時定量聚合酶連鎖反應 15 一、 RNA萃取 15 二、 互補鏈DNA反轉錄反應 15 三、 及時定量聚合酶連鎖反應 16 第八節、果蠅產蛋量試驗 17 第九節、果蠅食物攝取量試驗 17 第十節、果蠅腸道酸鹼值試驗 17 第十一節、果蠅三酸甘油酯定量 17 第十二節、果蠅體重測試 18 第十三節、果蠅飢餓耐受性測試 18 第十四節、統計分析 18 第三章 實驗結果 19 第一節、 突變株果蠅M2之壽命與突變位置探討 19 第二節、 Genetic background對突變果蠅M2的影響 25 第三節、 Vha16-1在果蠅中表現的位置 31 第四節、 M2果蠅之腸道功能分析 33 第五節、 M2果蠅之能量儲存探討 38 第四章 討論 42 第五章 結論 46 參考文獻 47 附錄一、V-ATPase之組成與結構 IX 附錄二、果蠅成蟲腸道構造圖 X 附錄三、Inverse PCR產物定序圖譜 XI zh_TW dc.language.iso en_US - dc.source.uri (資料來源) http://thesis.lib.nccu.edu.tw/record/#G0098754008 en_US dc.subject (關鍵詞) 突變生成 zh_TW dc.subject (關鍵詞) 壽命 zh_TW dc.subject (關鍵詞) 肥胖 zh_TW dc.subject (關鍵詞) 腸道酸化 zh_TW dc.subject (關鍵詞) mutagenesis en_US dc.subject (關鍵詞) lifespan en_US dc.subject (關鍵詞) obesity en_US dc.subject (關鍵詞) gut acidification en_US dc.title (題名) Vha16-1對果蠅腸道功能和壽命之調控 zh_TW dc.title (題名) Vha16-1 regulates intestinal function and lifespan in Drosophila melanogaster en_US dc.type (資料類型) thesis en dc.relation.reference (參考文獻) Allan AK, Du J, Davies SA, Dow JA (2005) Genome-wide survey of V-ATPase genes in Drosophila reveals a conserved renal phenotype for lethal alleles. 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