Role of Activating Protein 1 in Skeletal Myogenesis

在拟议的工作中，我们试图了解哺乳动物骨骼肌细胞发育的基础事件。细胞的承诺，成为专门的肌肉细胞需要一个特定的整体的基因表达，这是需要这些细胞有专门的功能，如能够合同（允许移动），对来自神经系统的神经脉冲做出反应（运动的自主控制），并作为能量底物如葡萄糖和脂肪的储存和燃烧的代谢库（代谢控制）。 为了调节这些“肌肉特异性”基因的表达，细胞核中存在蛋白质 它们被称为转录因子，物理上附着在基因上并决定哪些基因被表达（转录）。这些蛋白质通过直接结合DNA中的控制区域来发挥作用。在我们的研究中，我们特别感兴趣的是一种名为Fra2的蛋白质，它作为转录调节因子发挥这种功能。迄今为止，我们的研究表明，Fra2可能是控制胚胎骨骼肌形成的转录因子网络的重要组成部分。最近的研究还表明Fra2与卫星细胞有关，卫星细胞是一种有助于修复成人骨骼肌的干细胞。 因此，我们的研究旨在了解Fra2如何调节与其他因子相关的转录，以及Fra2特异性靶向基因组中的哪些基因，因为基因组中只有一小部分基因会受到调节。因此，我们将使用蛋白质组学中最先进的方法，如质谱法，来表征Fra2相互作用的蛋白质，我们将使用现代基因组分析方法来鉴定Fra2相互作用的基因。结合这些策略将有助于阐明Fra2蛋白在骨骼肌发育和纳塔尔后生理学中的功能。

In the proposed work we are attempting to understand the events underlying the development of cells that give rise to skeletal muscle in mammals. The commitment of cells to become specialized as muscle cells requires a particular ensemble of genes to be expressed which are required for these cells to have specialized functions such as being able to contract (allowing movement), to respond to nerve impulses from the nervous system (voluntary control of movement) and to function as a metabolic depot for the storage and combustion of energy substrates such as glucose and fats (metabolic control). In order to regulate the expression of these "muscle-specific" genes there are proteins in the nucleus called transcription factors which physically attach to and determine which genes are expressed (transcribed). These proteins function by directly binding to control regions in the DNA. In our studies we are particularly interested in a protein called Fra2 which functions in this capacity as a regulator of transcription. Our studies to date indicate that Fra2 may be an important part of a network of transcription factors controlling the formation of skeletal muscle in the embryo. Recent work has also implicated Fra2 in satellite cells which are stem cells that contribute to the repair of skeletal muscle in the adult. Our studies are thus aimed at understanding how Fra2 regulates transcription in association with other factors, and also which genes Fra2 specifically targets in the genome since only a fraction of the genes in the genome will be regulated. We will therefore use state of the art approaches in proteomics, such as mass spectrometry, to characterize the proteins that Fra2 interacts with and we will use modern approaches to genome analysis to identify the genes that Fra2 interacts with. In combination these strategies will help to elucidate the function of Fra2 protein in skeletal muscle development and post natal physiology.