本文主要研究内容
作者蓝剑锋（2019）在《秀丽线虫由同时抑制IGF-1和TOR信号通路产生的超级长寿表型的分子机制研究》一文中研究指出：近年来,对于衰老的分子机制的研究已取得了令人瞩目的进展。研究发现衰老被高度保守的信号通路所调控。其中,雷帕霉素受体信号通路和胰岛素/胰岛素类生长因子信号通路在几乎所有被研究过的生物中对衰老起着重要的调节作用。这两条高度保守的信号通路主要通过在转录和翻译水平调节下游基因的表达。之前研究发现在秀丽线虫中同时抑制这两条通路的daf-2rsks-1突变体表现出长达近五倍的协同性寿命延长。这种长寿现象是由AMPK介导的正反馈激活转录因子而实现的,而且进一步研究发现生殖腺组织可以对DAF-16(FOXO)进行细胞非自主性调节来参与衰老。研究表明核糖体S6激酶在翻译水平可以调节着很多重要基因的表达。虽然已有研究显示在多个物种中抑制mRNA的翻译均能有效延长衰老,但是其潜在的分子机制目前尚不清楚。为了弄清楚daf-2rsks-1突变体到底在翻译水平发生着怎样的变化,而且这些变化又是如何以组织特异性的方式影响衰老,从而进一步阐明daf-2rsks-1双突变体长达近五倍的寿命延长的分子机制。在这里,我们通过polysomal profiling和RNA-Seq比较野生型N2和daf-2 rsks-1突变体中在翻译水平受调节的基因,并分析研究这些基因在衰老中的作用以及其翻译调控。通过筛选发现这些基因在发育过程中起着至关重要的作用,大部分主要编码各类核糖体亚基。另外发现筛选中最显著的寿命延长表型是由于抑制了编码高度保守的细胞色素c亚基的基因cyc-2.1产生的。抑制细胞色素c的表达促进代谢器官肠道组织中的线粒体分裂且可以显著性的延长线虫的寿命,而这种寿命延长作用是依赖于线粒体未折叠蛋白反应(UPRmt)和AMPK的激活。另一方面,组织特异性分析显示cyc-2.主要在生殖腺中起寿命调节作用,特异的在生殖腺中抑制cyc-2.1可细胞非自主性激活肠组织中的UPRmt和AMPK的磷酸化。相对于野生型N2,CYC-.2.1的蛋白水平在daf-2 rsks-1突变体的生殖腺中显著性降低。我们还发现在daf-2 rsks-1突变体的肠道中有UPRmt激活的现象,并且证明了这UPRmt水平的提高正是超级长寿表型所必需的。进一步的生物信息学分析发现RNA结合蛋白GLD-1在daf-2 rsks-1突变体中的蛋白水平是上调的,预示着GLD-1可能是一个潜在的可以对cyc-2.1进行翻译调控的关键调节子。随后的功能性研究证实了在daf-2 rsks-1突变体的生殖腺中,mRNA翻译负调控因子GLD-1的蛋白水平上调,从而抑制了细胞色素c的翻译并激活了代谢器官中的线粒体应激。通过RNAi的手段敲降gld-1或者UPRmt信号通路中的关键转录因子均可显著性的缩短daf-2 rsks-1双突变的超长寿命。总的来说,该研究发现了 mRNA翻译介导的调控衰老的新机制,有助于阐明高度保守的雷帕霉素受体信号通路和胰岛素/胰岛素类生长因子信号通路下游的翻译控制网络。此外,该研究还发现了线粒体的应激信号可以通过生殖腺-肠道这种组织非特异性的方式进行传递,对这些信号的进一步研究将有助于阐明机体是如何协同生殖与代谢,从而在整体水平调控衰老这一复杂的生物学过程。另外,本研究中发现的关键基因都是在进化上高度保守的,由此可见在其他高等生物中可能也存在类似的调控机制。对于这些问题的深入探讨,将有助于我们理解衰老的本质,并能为治疗衰老相关疾病提供新的靶点与思路。
Abstract
jin nian lai ,dui yu cui lao de fen zi ji zhi de yan jiu yi qu de le ling ren zhu mu de jin zhan 。yan jiu fa xian cui lao bei gao du bao shou de xin hao tong lu suo diao kong 。ji zhong ,lei pa mei su shou ti xin hao tong lu he yi dao su /yi dao su lei sheng chang yin zi xin hao tong lu zai ji hu suo you bei yan jiu guo de sheng wu zhong dui cui lao qi zhao chong yao de diao jie zuo yong 。zhe liang tiao gao du bao shou de xin hao tong lu zhu yao tong guo zai zhuai lu he fan yi shui ping diao jie xia you ji yin de biao da 。zhi qian yan jiu fa xian zai xiu li xian chong zhong tong shi yi zhi zhe liang tiao tong lu de daf-2rsks-1tu bian ti biao xian chu chang da jin wu bei de xie tong xing shou ming yan chang 。zhe chong chang shou xian xiang shi you AMPKjie dao de zheng fan kui ji huo zhuai lu yin zi er shi xian de ,er ju jin yi bu yan jiu fa xian sheng shi xian zu zhi ke yi dui DAF-16(FOXO)jin hang xi bao fei zi zhu xing diao jie lai can yu cui lao 。yan jiu biao ming he tang ti S6ji mei zai fan yi shui ping ke yi diao jie zhao hen duo chong yao ji yin de biao da 。sui ran yi you yan jiu xian shi zai duo ge wu chong zhong yi zhi mRNAde fan yi jun neng you xiao yan chang cui lao ,dan shi ji qian zai de fen zi ji zhi mu qian shang bu qing chu 。wei le long qing chu daf-2rsks-1tu bian ti dao de zai fan yi shui ping fa sheng zhao zen yang de bian hua ,er ju zhe xie bian hua you shi ru he yi zu zhi te yi xing de fang shi ying xiang cui lao ,cong er jin yi bu chan ming daf-2rsks-1shuang tu bian ti chang da jin wu bei de shou ming yan chang de fen zi ji zhi 。zai zhe li ,wo men tong guo polysomal profilinghe RNA-Seqbi jiao ye sheng xing N2he daf-2 rsks-1tu bian ti zhong zai fan yi shui ping shou diao jie de ji yin ,bing fen xi yan jiu zhe xie ji yin zai cui lao zhong de zuo yong yi ji ji fan yi diao kong 。tong guo shai shua fa xian zhe xie ji yin zai fa yo guo cheng zhong qi zhao zhi guan chong yao de zuo yong ,da bu fen zhu yao bian ma ge lei he tang ti ya ji 。ling wai fa xian shai shua zhong zui xian zhe de shou ming yan chang biao xing shi you yu yi zhi le bian ma gao du bao shou de xi bao se su cya ji de ji yin cyc-2.1chan sheng de 。yi zhi xi bao se su cde biao da cu jin dai xie qi guan chang dao zu zhi zhong de xian li ti fen lie ju ke yi xian zhe xing de yan chang xian chong de shou ming ,er zhe chong shou ming yan chang zuo yong shi yi lai yu xian li ti wei she die dan bai fan ying (UPRmt)he AMPKde ji huo 。ling yi fang mian ,zu zhi te yi xing fen xi xian shi cyc-2.zhu yao zai sheng shi xian zhong qi shou ming diao jie zuo yong ,te yi de zai sheng shi xian zhong yi zhi cyc-2.1ke xi bao fei zi zhu xing ji huo chang zu zhi zhong de UPRmthe AMPKde lin suan hua 。xiang dui yu ye sheng xing N2,CYC-.2.1de dan bai shui ping zai daf-2 rsks-1tu bian ti de sheng shi xian zhong xian zhe xing jiang di 。wo men hai fa xian zai daf-2 rsks-1tu bian ti de chang dao zhong you UPRmtji huo de xian xiang ,bing ju zheng ming le zhe UPRmtshui ping de di gao zheng shi chao ji chang shou biao xing suo bi xu de 。jin yi bu de sheng wu xin xi xue fen xi fa xian RNAjie ge dan bai GLD-1zai daf-2 rsks-1tu bian ti zhong de dan bai shui ping shi shang diao de ,yu shi zhao GLD-1ke neng shi yi ge qian zai de ke yi dui cyc-2.1jin hang fan yi diao kong de guan jian diao jie zi 。sui hou de gong neng xing yan jiu zheng shi le zai daf-2 rsks-1tu bian ti de sheng shi xian zhong ,mRNAfan yi fu diao kong yin zi GLD-1de dan bai shui ping shang diao ,cong er yi zhi le xi bao se su cde fan yi bing ji huo le dai xie qi guan zhong de xian li ti ying ji 。tong guo RNAide shou duan qiao jiang gld-1huo zhe UPRmtxin hao tong lu zhong de guan jian zhuai lu yin zi jun ke xian zhe xing de su duan daf-2 rsks-1shuang tu bian de chao chang shou ming 。zong de lai shui ,gai yan jiu fa xian le mRNAfan yi jie dao de diao kong cui lao de xin ji zhi ,you zhu yu chan ming gao du bao shou de lei pa mei su shou ti xin hao tong lu he yi dao su /yi dao su lei sheng chang yin zi xin hao tong lu xia you de fan yi kong zhi wang lao 。ci wai ,gai yan jiu hai fa xian le xian li ti de ying ji xin hao ke yi tong guo sheng shi xian -chang dao zhe chong zu zhi fei te yi xing de fang shi jin hang chuan di ,dui zhe xie xin hao de jin yi bu yan jiu jiang you zhu yu chan ming ji ti shi ru he xie tong sheng shi yu dai xie ,cong er zai zheng ti shui ping diao kong cui lao zhe yi fu za de sheng wu xue guo cheng 。ling wai ,ben yan jiu zhong fa xian de guan jian ji yin dou shi zai jin hua shang gao du bao shou de ,you ci ke jian zai ji ta gao deng sheng wu zhong ke neng ye cun zai lei shi de diao kong ji zhi 。dui yu zhe xie wen ti de shen ru tan tao ,jiang you zhu yu wo men li jie cui lao de ben zhi ,bing neng wei zhi liao cui lao xiang guan ji bing di gong xin de ba dian yu sai lu 。
论文参考文献
论文详细介绍
论文作者分别是来自南京大学的蓝剑锋，发表于刊物南京大学2019-12-19论文，是一篇关于衰老论文,胰岛素类生长因子受体论文,核糖体激酶论文,翻译论文,线粒体未折叠蛋白反应论文,秀丽线虫论文,南京大学2019-12-19论文的文章。本文可供学术参考使用，各位学者可以免费参考阅读下载，文章观点不代表本站观点，资料来自南京大学2019-12-19论文网站，若本站收录的文献无意侵犯了您的著作版权，请联系我们删除。
标签：衰老论文; 胰岛素类生长因子受体论文; 核糖体激酶论文; 翻译论文; 线粒体未折叠蛋白反应论文; 秀丽线虫论文; 南京大学2019-12-19论文;