Mechanisms of Aging in C. elegans

线虫的衰老机制

基本信息

批准号：
8811904
负责人：
STUART K KIM
金额：
$ 31.22万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2016-02-29
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): This proposal is about intrinsic mechanisms of aging, which are inherent and always occur during the normal aging process. Intrinsic mechanisms involve an internal clock that specifies lifespan during normal aging. Besides damage accumulation, another mechanism for intrinsic aging has recently been found in C. elegans termed developmental drift. Developmental pathways are established in the young adult to guide the formation of different tissues. Key regulators of these developmental pathways become aberrantly expressed in old age, leading to a cascade of changes in expression of downstream genes that has detrimental effects on tissue function and that limits lifespan. Developmental drift is conceptually novel because it proposes that that old worms are not the same as young worms with damage accumulation. Rather, old worms have inherent, programmed differences that make them more susceptible to degeneration and death. This proposal uses C. elegans as a model system because of its short two week lifespan and powerful genetic tools. DNA microarray experiments have been used to define a molecular signature for aging that includes 1254 genes that differ in expression between young and old worms. Seven transcription factors have previously been identified as candidates that may be responsible for these age-related changes. All seven transcription factors are key regulators of development in diverse tissues, such as the intestine and the skin. This proposal will use ChIP SEQ experiments to determine whether these transcription factors are directly responsible for causing expression of their downstream genes to change with age. Expression experiments using an automatic cell lineage analyzer to digitize images of GFP-expressing worms will be used to extract precise expression data from individual cells. These data will show how expression of the seven transcription factors changes with age. Transgenic worms will be engineered to convert old worms into young worms; specifically, expression of the seven aging regulators in old worms will be altered to resemble expression found in young worms, and then lifespan experiments will be used to test whether converting worms to their younger state is beneficial. A key prediction of the developmental drift hypothesis is that changes in old age should resemble changes that occur during development. This will be tested by finding out if the network of genes directly downstream of a transcription factor during aging are the same as its downstream network during development.

描述（由申请人提供）：该提案是关于衰老的内在机制，这些机制是固有的，并且总是在正常衰老过程中发生。内在机制涉及指定正常衰老过程中寿命的内部时钟。除了损伤积累之外，最近还在秀丽隐杆线虫中发现了另一种内在衰老机制，称为发育漂移。年轻人建立了发育途径来指导不同组织的形成。这些发育途径的关键调节因子在老年时表达异常，导致下游基因表达发生一系列变化，对组织功能产生有害影响并限制寿命。发育漂移在概念上是新颖的，因为它提出老蠕虫与具有损伤积累的年轻蠕虫不同。相反，老蠕虫具有固有的、程序化的差异，使它们更容易退化和死亡。该提案使用秀丽隐杆线虫作为模型系统，因为它的寿命较短，只有两周，并且具有强大的遗传工具。 DNA 微阵列实验已被用来定义衰老的分子特征，其中包括 1254 个基因，这些基因在年轻和年老的线虫之间表达有所不同。先前已确定七个转录因子可能是导致这些与年龄相关的变化的候选因子。所有七种转录因子都是肠道和皮肤等多种组织发育的关键调节因子。该提案将使用 ChIP SEQ 实验来确定这些转录因子是否直接导致其下游基因的表达随年龄而变化。使用自动细胞谱系分析仪对表达 GFP 的蠕虫图像进行数字化的表达实验将用于从单个细胞中提取精确的表达数据。这些数据将显示七种转录因子的表达如何随年龄变化。转基因蠕虫将被改造，将老蠕虫转变为年轻蠕虫；具体来说，年老蠕虫中七种衰老调节因子的表达将被改变，以类似于年轻蠕虫中发现的表达，然后寿命实验将用于测试将蠕虫转变为年轻状态是否有益。发育漂移假说的一个关键预测是，老年时的变化应该类似于发育期间发生的变化。这将通过找出衰老过程中转录因子直接下游的基因网络是否与其发育过程中的下游网络相同来测试。