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都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，你肝脏的细胞与你大脑的细胞非常不同)。因此，这些遗传信息的解码和处理方式将随着细胞的不同而不同，反过来，这在很大程度上也是如何在我们的体内创造出令人难以置信的细胞多样性和组织复杂性的。这种对遗传信息的解码，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(包括被称为信使RNA或mRNAs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，我们建议研究一种被称为Staufen蛋白的高度保守的蛋白质家族，我们的团队最近在转录后过程中发现了一个新的功能，称为剪接‘产生mRNAs的过程’。施托芬最早是在果蝇中发现的，它被发现对正常的胚胎发育是必不可少的。从那时起，在包括哺乳动物在内的其他几种生物中发现了Staufen的同源物，并对其进行了表征，在这些生物中，它们被发现在基因表达途径中扮演多种角色。然而，在我们的工作之前，Staufen蛋白的作用从未被探索过。因此，我们在这里提出了一个研究计划，系统和全面地表征Staufen蛋白在前mRNA剪接中的这一新功能。作为第一个短期目标，我们将使用一系列复杂的生化方法，以更好地了解Staufen蛋白质如何影响剪接。作为第二个目标，我们将使用最先进的分子基因组学方法，精确地确定在特定细胞类型、组织和/或哺乳动物胚胎和出生后发育的不同阶段，斯陶芬调控其表达的所有基因。*总体而言，我们的研究将为斯陶芬蛋白调控剪接的分子机制(S)提供关键的新见解。鉴定由Staufen蛋白调控的全谱剪接靶标无疑将导致发现对正常组织分化和功能至关重要的新的调控途径。这些知识的进步将使更广泛的研究界受益。最后，我们的研究计划将有助于对该领域的高素质人员进行非常专业的培训，该领域有可能成为学术界以及公共和私营部门的变革性人员。

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.