Long non-coding RNA function during cellular ageing

在发达国家，衰老是大多数人类疾病的最大风险因素，包括阿尔茨海默氏症和帕金森氏症等进行性疾病、发病率可变的癌症等疾病，以及心脏病和中风等灾难性系统故障。随着我们年龄的增长，这些与年龄相关的疾病正在成为我们社会日益增加的负担。虽然对特定疾病过程的研究长期以来一直是生物医学研究的主要焦点，但人们越来越认识到将正常衰老过程本身作为问题的重要组成部分进行研究的重要性，并探索减缓或逆转其影响的方法。衰老是一个复杂的过程，可以看作是时间蹂躏的一个不可避免的特征。然而，最近的发现表明，通过简单的干预，衰老可以以惊人的方式得到改变。例如，基因操作或药物可以延缓衰老，改善实验动物晚年的健康状况。在不同的生物体中，衰老的过程是相似的，包括人类。老龄化研究的一个核心挑战仍然是了解调节健康寿命的生物因素。诸如衰老之类的生物过程受到基因组编码的遗传信息的影响。编码蛋白质的基因长期以来一直是研究的主要焦点，而最近的发现表明，基因组也包含许多不编码蛋白质的基因，而是所谓的非编码rna。已知功能的非编码rna在调节其他基因方面发挥着重要作用。但大多数非编码rna的作用尚不清楚。值得注意的是，一些非编码rna参与衰老和相关疾病的例子正在出现。然而，基因组调控和非编码rna如何影响健康寿命在很大程度上是未知的。因此，找出与衰老相关的非编码rna在从基因组到长寿的信息流中所起的作用是很重要的。利用裂变酵母作为一种简单而经济的模式生物，我们最近发现了一种令人着迷的非编码RNA，它在衰老过程中被上调，延长了酵母细胞的寿命。我们现在想研究这种非编码RNA在基因调控和衰老中的详细功能。值得注意的是，酵母和人类的基因调控和衰老是相似的，但在简单的酵母中更容易研究。酵母细胞在有限的营养条件下进入休眠、不分裂状态。这种休眠状态的转变提供了一个令人信服的细胞系统来分析与衰老相关的非编码RNA和影响这种状态下寿命的基因调控过程。我们已经创造了基因操纵的突变细胞，其中非编码RNA要么过多，导致细胞寿命较长，要么完全缺失，导致细胞寿命较短。为了研究我们的非编码RNA在衰老过程中的作用，我们将应用互补的全基因组方法，可以系统地确定所有基因的不同调控方面。我们还将把缺乏非编码RNA的细胞与缺乏不同蛋白质的细胞结合起来，研究这种双重突变对寿命的影响。这种有效的方法可以指出对非编码RNA功能很重要的生物过程。此外，我们将使用现有的方法来鉴定与我们的非编码RNA相互作用的基因、其他RNA或蛋白质，从而可能确定其功能。结合这些互补的方法将提供生物学功能的重要线索，然后我们将通过进一步的详细分析进行测试，以获得有关非编码RNA如何调节基因和寿命的丰富信息。我们预计，该项目将提供一个有价值的平台，以更好地了解非编码RNA功能在衰老过程中基因调控的普遍原理，这可能有助于最终开发出延长人类健康寿命的干预措施。

Ageing is the largest risk factor for most human diseases in developed countries, including progressive diseases such as Alzheimer's and Parkinson's, diseases like cancer that show variable rates of onset, and catastrophic system failures such as heart-attack and stroke. As we are getting older, these age-associated diseases are becoming an ever increasing burden for our society. While the study of specific disease processes has long been a major focus of biomedical research, there is a growing realisation of the importance to study the normal ageing process itself as an essential part of the problem, and to explore ways to slow or reverse its effects. Ageing is a complex process that can be seen as an inevitable feature of the ravages of time. Recent discoveries, however, demonstrate that ageing can be modified in dramatic ways by simple interventions. For example, genetic manipulations or drugs can delay ageing and improve health late in the life of laboratory animals. The processes involved in ageing are similar in different organisms, including humans. A central challenge of ageing research remains to understand biological factors regulating healthy lifespan. Biological processes such as ageing are influenced by the genetic information encoded in the genome. Genes coding for proteins have long been the main focus of research, while recent findings reveal that genomes also contain many genes that do not code for proteins but for so-called non-coding RNAs. The non-coding RNAs with known functions play critical roles in regulating other genes in different ways. But the roles of most non-coding RNAs are not yet known. Notably, several examples are emerging where non-coding RNAs are involved in ageing and associated diseases. However, how genome regulation and non-coding RNAs affect the healthy lifespan is largely unknown. It is therefore important to find out what roles ageing-associated non-coding RNAs play in the information flow from the genome to longevity. Using fission yeast as a simple and cost-effective model organism, we have recently discovered a fascinating non-coding RNA that becomes up-regulated during ageing and prolongs the lifespan of yeast cells. We now want to study the detailed function of this non-coding RNA in gene regulation and ageing. Remarkably, gene regulation and ageing are similar from yeast to human, but are much easier to study in the simple yeast. Yeast cells enter a dormant, non-dividing state under limiting nutrients. The transition to this dormant state provides a compelling cellular system to analyse our ageing-associated non-coding RNA and gene-regulatory processes affecting the lifespan in this state. We have created genetically manipulated mutant cells in which the non-coding RNA is either over-abundant, leading to long-lived cells, or completely absent, leading to short-lived cells. In order to study the role of our non-coding RNA during ageing, we will apply complementary genome-wide methods that can systematically determine different regulatory aspects for all genes. We will also combine cells that lack our non-coding RNA with cells that lack different proteins to study the effects of such double mutants on lifespan. This potent approach can point to biological processes that are important for non-coding RNA function. Moreover, we will use current methods to identify genes, other RNAs or proteins that interact with our non-coding RNA and thus may determine its function. Combining these complementary approaches will provide vital clues on biological functions, which we will then test with further detailed analyses to obtain rich information on how our non-coding RNA regulates genes and lifespan. We anticipate that this project will provide a valuable platform to better understand universal principles of non-coding RNA function for gene regulation during ageing, which could help to eventually develop interventions that extend healthy lifespan in humans.