Defining the Role of Staufen proteins in pre-mRNA Splicing

我们每个细胞的细胞核中都含有完全相同的遗传信息，这些信息被编码到我们的DNA中。然而，我们的大多数细胞在我们的身体中有不同的角色和功能，因为它们可以是非常不同的组织的一部分（例如，你的肝脏细胞和你的大脑细胞非常不同）。因此，基因信息的解码和处理方式会因细胞而异，反过来，这在很大程度上就是我们体内令人难以置信的细胞多样性和组织复杂性是如何产生的。这种基因信息的解码，我们称之为“基因表达”，涉及几个步骤，并在此过程中产生许多中间产物（包括称为信使rna或mrna的分子）。基因表达的第一步是转录，也是迄今为止研究最多的一步。我们的研究小组对转录后的基因表达步骤感兴趣，因此被称为“转录后过程”。******对于这里描述的研究计划，我们建议研究一个高度保守的蛋白质家族，称为“Staufen”蛋白质，我们的团队最近发现了一个名为“剪接”的转录后过程中的新功能，即“mrna”的产生过程。Staufen最初是在果蝇中发现的，它被发现是正常胚胎发育所必需的。从那时起，Staufen的同源物在包括哺乳动物在内的其他几种生物中被发现并表征，在这些生物中，它们被发现在基因表达途径中发挥多种作用。然而，在我们的工作之前，从未探索过Staufen蛋白的作用。******因此，我们在这里提出了一个研究计划，以系统和全面地表征Staufen蛋白在mrna前剪接中的这种新功能。作为第一个短期目标，我们将使用一系列复杂的生化方法，以便更好地了解Staufen蛋白如何影响剪接。作为第二个目标，我们将使用最先进的分子基因组学方法来精确识别在哺乳动物胚胎和产后发育的特定细胞类型、组织和/或不同阶段由Staufen控制表达的所有基因。******总的来说，我们的研究将为Staufen蛋白调节剪接的分子机制提供关键的新见解。Staufen蛋白调控的剪接靶点的全谱鉴定无疑将导致对正常组织分化和功能至关重要的新调控途径的发现。这些知识的进步将使更广泛的研究界受益。最后，我们的研究项目将有助于在一个有潜力成为学术界以及公共和私营部门变革的领域培养非常专业的高素质人才。

Each of our cells contain in their nucleus the exact same genetic information, encoded into our DNA. However, most of our cells have distinct roles and functions in our body, as they can be part of very distinct tissues (for example, the cells from your liver are very different from the cells in your brain). It is therefore how this genetic information is decoded and processed that will vary from cells to cells, and in turn, this is largely how the incredible cellular diversity and tissue complexity is created in our body. This decoding of genetic information, which we call ‘gene expression' involves several steps and generates many intermediates along the way (including molecule known as ‘messenger RNAs or mRNAs'). The first step of gene expression is transcription, and it is by far the most studied. Our research group is interested in steps of gene expression that are after transcription, and that are thus referred to as ‘post-transcriptional processes'.******For the research program described here we propose to study a family of highly conserved proteins known as ‘Staufen' proteins, for which our group has recently uncovered a new function in a post-transcriptional process termed ‘splicing' – the process by which ‘mRNAs' are produced. Staufen was first discovered in fruit flies, where it was found to be essential for proper embryonic development. Since then, homologs of Staufen have been discovered and characterized in several other organisms, including mammals, where they were found to play multiple roles along the gene expression pathway. However, a role for Staufen proteins was never explored before our work.******We thus propose here a research program to systematically and comprehensively characterize this novel function of Staufen proteins in pre-mRNA splicing. As a first short-term objective, we will use a series of sophisticated biochemical approaches in order to gain a better understanding of ‘how' Staufen proteins can impact on splicing. As a second objective, we will use state-of-the-art molecular genomics approaches to precisely identify all the genes for which expression is controlled by Staufen in specific cell types, tissues and/or at various stages during mammalian embryonic and post-natal development.******Overall, our studies will provide key new insights into the molecular mechanism(s) by which Staufen proteins regulate splicing. The identification of the full spectrum of splicing targets regulated by Staufen proteins will undoubtedly lead to the discovery of novel regulatory pathways crucial for normal tissue differentiation and function. These advances in knowledge will benefit the broader research community. Finally, our research program will contribute to the very specialized training of highly qualified personnel in a field that has the potential to become transformative for academia as well as the public and private sectors.