Epigenetic Silencing of Retroelements in Mammalian Stem Cells: a role for RNA interference?

既然人类基因组已经被测序了，所有构成我们细胞的基因都已经被定义了。一个主要问题仍然存在：所有这些基因是如何被控制和协调的？是什么在正确的时间开启或关闭它们？在这个项目中，我们希望测试一种在植物和苍蝇中新发现的关闭基因的机制是否也适用于哺乳动物。如果我们证明了这一机制，那么它可能有助于我们改进基因治疗——一种用健康基因代替细胞中有缺陷基因的新型医学治疗形式。遗传疾病，如血友病，以及获得性疾病，如癌症，都被认为是基因治疗的合适目标。然而，令人惊讶的是，基因治疗的前景并没有达到人们的预期。在试图获得临床相关结果的过程中，病毒（迫使受感染细胞听从它们的命令的大师）已经被利用来将健康基因传递到患病细胞中。一个主要问题是，临床使用的经过修饰的安全病毒在持续生产健康基因产品方面效率不高。在研究什么关闭基因的问题时，我们将通过定义关闭基因治疗病毒的机制来解决基因治疗的可持续性问题。如果我们能够理解是什么关闭了细胞中的病毒基因，那么我们应该能够设计出避免“关闭开关”的方法，从而为许多类型的癌症提供持久的治疗方法。在所描述的研究中，我们将使用许多不同但互补的方法来解决这个问题。

Now that the human genome has been sequenced, all the genes which encode the bricks and mortar of our cells have been defined. A major question remains: how are all these genes controlled and co-ordinated? What turns them on or off at precisely the right time? In this project we wish to test whether a newly-discovered mechanism of turning genes off in plants and flies also works in mammals. If we demonstrate this mechanism then it may help us to improve gene therapy - a novel form of medical treatment in which healthy genes are used to replace defective genes in cells. Both inherited diseases, like hemophilia, and acquired diseases, like cancer, have been considered appropriate targets for gene therapies. Surprisingly, however, the promises of gene therapy have not kept up with expectations. In attempting to achieve clinically relevant results, viruses (masters of forcing infected cells to do their bidding) have been harnessed to deliver healthy genes into diseased cells. A major problem has been that the modified, safe viruses used clinically have not been efficient at achieving sustained production of healthy gene products. In examining the question of what turns gene off, we will attack the problem of sustainability of gene therapy by defining the mechanisms involved in switching gene therapy viruses off. If we can understand what switches viral genes off in cells, then we should be able to devise means to avoid the 'off switch' and thereby provide durable treatments for many types of cancer. In the studies described , we will attack this problem using a number of different, but complementary approaches.