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The evolution and molecular basis of adaptations to Telomere Biology in immortal worms.

永生蠕虫端粒生物学适应的进化和分子基础。

基本信息

批准号：
BB/K007564/1
负责人：
Aziz Aboobaker
金额：
$ 80.71万
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2013
资助国家：
英国
起止时间：
2013 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FK007564%2F1
关键词：
evolution molecular basis adaptations Telomere

项目摘要

We all get older. As we do our body's ability to repair itself after everyday wear and tear slows down. Many acute and chronic diseases associated with ageing are a result of our bodies cells failing to renew themselves and this in turn reduces the effectiveness of our various tissues and organs to levels that are unhealthy, collectively these are degenerative diseases. Another set of diseases associated with getting older are those where our cells cycle out of control and form tumours. In fact one theory of ageing suggests that it is in fact a trade off between allowing our cells to cycle and replace and repair damage and the need to limit their ability to replicate so that they don't cycle out of control. Thus our normal healthy cells are limited in the number of times they can divide, and when these divisions have been used up they enter a state called "senescence". The number of cell divisions is linked to cells becoming senescent through the mechanism that copies DNA. Every cell cycle our DNA must be copied so that one copy can be given to each cell. As this happens the strings of DNA in our cells get shorter each cycle. The ends of of our DNA strings have special repeated DNA sequences, 1000s of copies of the base sequence TTAGGG, at the ends called "telomeres". These sequences are added by a enzyme called "telomerase". Telomeres normally act as protective caps to our DNA strings, and its is the telomere sequences that get shorter every time a cell divides. When these repeat sequences reach a critically short length signals from the telomeres tell the cell to become senescent. This is one potential molecular process that leads to ageing. Significantly, the importance of senescence is illustrated by the fact that most cancers are formed by cells that have escaped senescence and inappropriately activated the enzyme telomerase so that DNA ends are maintained when they shouldn't be.Some animals seem to live for a very long time and others appear not to age at all. How do these animals do this? Do their cells age and senesce like ours do? If not how do they manage this? Given the significance of the ageing process in our society we believe that studying these animals may prove to be significant for understanding key genetic processes of ageing.For this reason we work with "immortal" worms called planarians or flatworms. These particular animals mostly live in freshwater or damp land habitats and appear to have an indefinite capacity to regenerate. This means that they repair any damage or injury to reconstitute fully functional animals. For example decapitated animals will regenerate the head including the brain. Underpinning this ability is a population of adult stem cells that are spread through the bodies of these worms. These cells are able to replace all cell types in the bodies of these worms and seem to keep dividing indefinitely. In fact we think that these animals may potentially be effectively IMMORTAL by avoiding cellular senescence. We have taken a preliminary look at whether their telomeres get shorter. We have found that worms are able to stop there DNA form shortening as cells divide, and we think this maybe how they avoid senescence. They do this by activating the enzyme telomerase in response to damage or injury that induces their stem cells to proliferate. At first glance this seem like a satisfying answer but actually we don't know how this is controlled or how this scenario evolved. Another important question is whether planarians are more susceptible to tumours if their cells can keep dividing? If so how do these animals deal with this risk? In this study we will investigate the telomere biology of these mazing animals to see how they seem to avoid both senescence (ageing). We don't really know exactly what we expect to find, but we are sure the results will be exciting. To learn more about planarians and our work please visit www.aboobakerlab.com

我们都会变老。当我们这样做时，我们身体在日常磨损后自我修复的能力会减慢。许多与衰老相关的急慢性疾病是由于我们的身体细胞不能自我更新的结果，这反过来又将我们各种组织和器官的有效性降低到不健康的水平，统称为退行性疾病。另一组与变老有关的疾病是细胞周期失控并形成肿瘤。事实上，一种关于衰老的理论表明，这实际上是一种权衡，一方面允许我们的细胞循环、替换和修复损伤，另一方面需要限制它们的复制能力，使它们不会失去控制。因此，我们正常的健康细胞分裂的次数是有限的，当这些分裂耗尽时，它们就会进入一种称为“衰老”的状态。细胞分裂的数量通过复制DNA的机制与细胞衰老有关。在每个细胞周期中，我们的DNA必须被复制，这样才能给每个细胞一个拷贝。当这种情况发生时，我们细胞中的DNA串每个周期都会变短。我们的DNA序列的末端有特殊的重复DNA序列，即碱基序列TTAGGG的上千个拷贝，末端被称为“端粒”。这些序列是由一种名为“端粒酶”的酶添加的。端粒通常是我们DNA序列的保护帽，它是细胞每次分裂时变短的端粒序列。当这些重复序列达到非常短的长度时，来自端粒的信号告诉细胞衰老。这是导致衰老的一个潜在的分子过程。值得注意的是，衰老的重要性体现在以下事实上：大多数癌症是由逃脱衰老的细胞形成的，它们不适当地激活了端粒酶，使DNA末端在不应该衰老的情况下保持不变。一些动物似乎活了很长时间，另一些动物似乎根本不衰老。这些动物是如何做到这一点的？他们的细胞会像我们一样衰老吗？如果没有，他们是如何做到这一点的？鉴于衰老过程在我们的社会中的重要性，我们认为研究这些动物对于理解衰老的关键遗传过程可能被证明是重要的。因此，我们研究了被称为行星虫或扁虫的“不朽”蠕虫。这些特殊的动物大多生活在淡水或潮湿的陆地栖息地，似乎具有无限的再生能力。这意味着它们修复任何损伤或伤害，以恢复完全功能的动物。例如，被斩首的动物会再生头部，包括大脑。支撑这种能力的是一群成体干细胞，它们通过这些蠕虫的身体传播。这些细胞能够取代这些蠕虫体内的所有细胞类型，并似乎继续无限期地分裂。事实上，我们认为这些动物可能通过避免细胞衰老而有效地长生不老。我们初步观察了它们的端粒是否变短了。我们已经发现，蠕虫能够阻止DNA在细胞分裂时缩短，我们认为这可能是它们避免衰老的原因。他们通过激活端粒酶来应对损伤或损伤，从而诱导干细胞增殖。乍一看，这似乎是一个令人满意的答案，但实际上我们不知道这是如何控制的，也不知道这种情况是如何演变的。另一个重要的问题是，如果他们的细胞能够继续分裂，他们是否更容易患上肿瘤？如果是这样，这些动物是如何应对这种风险的？在这项研究中，我们将研究这些迷宫动物的端粒生物学，以了解它们似乎如何避免衰老(衰老)。我们真的不知道我们希望找到什么，但我们相信结果将是令人兴奋的。要了解更多关于大行星和我们的工作的信息，请访问www.attobakerLab.com

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The genome of the crustacean Parhyale hawaiensis, a model for animal development, regeneration, immunity and lignocellulose digestion.

DOI：
10.7554/elife.20062
发表时间：
2016-11-16
期刊：
eLife
影响因子：
7.7
作者：
Kao D;Lai AG;Stamataki E;Rosic S;Konstantinides N;Jarvis E;Di Donfrancesco A;Pouchkina-Stancheva N;Sémon M;Grillo M;Bruce H;Kumar S;Siwanowicz I;Le A;Lemire A;Eisen MB;Extavour C;Browne WE;Wolff C;Averof M;Patel NH;Sarkies P;Pavlopoulos A;Aboobaker A
通讯作者：
Aboobaker A

Planarian MBD2/3 is required for adult stem cell pluripotency independently of DNA methylation.

成年干细胞多能与DNA甲基化独立于成年干细胞多能性是必需的。

DOI：
10.1016/j.ydbio.2013.09.020
发表时间：
2013-12-01
期刊：
DEVELOPMENTAL BIOLOGY
影响因子：
2.7
作者：
Jaber-Hijazi, Farah;Lo, Priscilla J. K. P.;Mihaylova, Yuliana;Foster, Jeremy M.;Benner, Jack S.;Romero, Belen Tejada;Chen, Chen;Malla, Sunir;Solana, Jordi;Ruzov, Alexey;Aboobaker, A. Aziz
通讯作者：
Aboobaker, A. Aziz

Microbe-mediated host defence drives the evolution of reduced pathogen virulence.