Computational Analysis of Transcription and Alternative Splicing Events in Squamous Cell Cancer.

鳞状细胞癌（SCC）是一种非常常见的人类癌症，影响身体表面，如皮肤，子宫颈（子宫颈）以及口腔和喉咙的衬里。在为这些重要的癌症寻找新的和成功的治疗方法方面几乎没有进展，尽管最近的研究有针对驱动SCC发生的基因组的药物确实有帮助。我将详细研究SCC如何受到一种称为“RNA选择性剪接”的过程的影响。我们细胞中的DNA包含一种代码，该代码被“读取”以产生称为RNA的信使分子。基因是转化为RNA的有用的编码，在每个基因中，信息的“单词”与不相关的编码区域交替出现。为了得到一个有意义的信息，有用的词需要被“拼接”在一起，不相关的比特被拼接出来。这个过程被称为RNA剪接。在某些基因中，通过“选择性RNA剪接”，一组DNA单词可以产生不止一个有意义的信息。这可能是细胞正常功能的一部分，但如果它出错，它可能会破坏产生的信息，可能使细胞功能不佳或失控（如癌症）。控制这种剪接涉及复杂的蛋白质混合物，包括“剪接因子”和“RNA结合蛋白”。RNA剪接在癌细胞中发生变化，但对于个别癌症类型，我们不了解变化的全部范围，也不知道哪种变化是新治疗或测试的最佳靶点。我将确定SCC常见的剪接变化，以及特定于特定部位和/或原因的剪接变化。我将研究来自患者SCC的样本，这些样本来自身体的两个不同部位-皮肤和子宫颈。这些都有不同的原因，特别是皮肤中的阳光和子宫颈中的病毒感染（人乳头瘤病毒）。我将使用强大的新技术来读取样本中所有RNA分子的序列。我将加入欧洲生物信息学研究所（EBI）和剑桥大学之间的独特合作。我将与Anton Enright博士一起在EBI工作，EBI是剑桥附近的一个世界知名的生物计算中心，我将在剑桥大学病理学系Nicholas科尔曼教授的实验室中承担该项目的实验和临床方面。这些高度互补的环境将为我提供一个理想的平台，让我成功地完成这项工作，并发展我作为一名学术医生的职业生涯。利用美国大型项目的基因研究数据库，我将能够看到我发现的变化是否会对癌症患者的生存时间和对药物的反应产生影响。这些数据库包含各种癌症的信息，包括各种SCC，但没有正常健康组织的信息-这就是为什么需要这个项目。我生成的所有结果都将通过一个可以通过互联网访问的安全数据库公开提供，任何人都可以免费阅读我基于这项工作发表的任何科学论文。我的项目将大大提高我们对RNA剪接如何在SCC癌细胞中起作用，并将识别具有特定原因和/或发生在体内特定部位的SCC之间的差异。这项工作将为诊断和/或治疗各种常见的SCC开辟新的机会。

Squamous cell carcinomas (SCCs) are a very common type of human cancer which affect surface in the body, such as the skin, cervix (neck of the womb) and the lining of the mouth and throat. There has been little progress towards finding new and successful treatments for these important cancers, although recent studies have drugs which target sets of genes that drive the SCC to occur do help. I will study in detail how SCCs are affected by a process called "alternative RNA splicing".The DNA in our cells contains a code which is 'read' to make messenger molecules called RNA. The useful bit of the code which is turned into RNA are the genes, and within each gene, the 'words' of the message are alternated with areas of irrelevant code. To get a meaningful message, the useful words need to be 'spliced' together and the irrelevant bits spliced out. That process is called RNA splicing. In some genes, more than one meaningful message can be made from one set of DNA words by 'alternative RNA splicing'. That can be part of how cells function normally, but if it goes wrong it can damage the message produced, potentially making a cell function less well or to grow out of control (as in cancer). Controlling this splicing involves a complex mix of proteins, including 'splicing factors' and 'RNA binding proteins'. RNA splicing is changed in cancer cells but for individual cancer types, we do not understand the full range of the changes, nor which of them would make the best targets for new treatments or tests.I will identify splicing changes that are common to SCCs, and also those that are specific to a particular site and/or cause. I will look at samples from patients' SCCs that come from two different sites in the body - the skin and the cervix. These have different causes, particularly sunlight in the skin and infection with a virus (the human papillomavirus) in the cervix.I will use powerful new technologies to read the sequence of all the RNA molecules in the samples. I will join a unique collaboration between the European Bioinformatics Institute (EBI) and Cambridge University. I will be based with Dr Anton Enright at the EBI, a world-renowned centre for biological computing near Cambridge, and will undertake the experimental and clinical aspects of the project in the laboratory of Professor Nicholas Coleman at Cambridge University Department of Pathology. Together, these highly complementary environments will provide me with the ideal platform to complete this work successfully and to develop my career as an academic doctor.Using databases of gene studies from large projects in America, I will be able to see if the changes I've found make a difference to how long patients with cancer survive and respond to drugs. These databases have information for a wide range of cancers, including various SCCs, but none for normal, healthy tissue - which is why this project is needed.All the results I generate will be made available openly using a secure database that can be accessed through the internet, and any scientific papers that I publish based on this work will be freely available to anyone to read.My project will greatly improve our understanding of how RNA splicing works in SCC cancer cells and will identify differences between SCCs that have particular causes and/or occur at specific sites in the body. The work will open up new opportunities for diagnosing and/or treating a variety of common SCCs.