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基因表达的步骤感兴趣，因此被称为“转录后过程”。

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.