The control of C/EBPbeta DNA-binding affinity by retinoic acid and Smad3 during mesenchymal stem cell differentiation

组成脂肪、骨软骨和肌肉的细胞可以从一种称为间充质干细胞的干细胞中产生。研究表明，维生素A可以防止新的脂肪细胞的形成，并有助于产生更多的骨骼细胞。我们已经证明，维生素A可以在分子水平上通过一种名为C/EBPbeta的蛋白质发挥作用。C/EBPbeta的作用是利用DNA制造将干细胞转化为成熟骨或脂肪细胞所需的新蛋白质。我们发现，另一种蛋白质SMAD3在维生素A处理的干细胞中表达水平更高，我们认为这种蛋白质参与阻止C/EBPbeta与DNA相互作用，这是它活跃所必需的。这项建议旨在了解维生素A如何通过Smad3干扰C/EBPβ活性来阻止脂肪细胞的形成和增强骨细胞的产生。我们将(1)评估Smad3在脂肪细胞和骨细胞形成过程中对C/EBPbeta活性的干扰；(2)表征Smad3和C/EBPbeta如何在细胞中相互作用，并最终(3)确定受这一过程调控的新基因。这项工作的结果将帮助我们更好地了解维生素A是如何控制细胞功能的，以及间充质干细胞成熟是如何受到调控的--本质上提供了关于脂肪和骨细胞如何在体内形成的宝贵信息。

Cells that make up fat, bone cartilage and muscle, can be generated from a single stem cell called a mesenchymal stem cell. Research has shown that vitamin A can prevent to formation of new fat cells and can help produce more bone cells. We have shown that vitamin A can act, at a molecular level, through a protein called C/EBPbeta. C/EBPbeta's role is to use DNA to make new proteins required to convert stem cells into mature bone or fat cells. We have discovered that another protein, Smad3, is expressed at higher levels in stem cells treated with vitamin A, and we believe this protein is involved in preventing C/EBPbeta from interacting with DNA, something it needs to do to be active. This proposal aims to understand how vitamin A blocks fat cell formation and enhances bone cell production through Smad3 interference with C/EBPbeta activity. We will (1) assess Smad3 interference of C/EBPbeta activity during fat cell and bone cell formation; (2) Characterize how Smad3 and C/EBPbeta interact in the cell and finally (3) identify new genes that are regulated by this process. The results of this work will help us better understand how vitamin A controls cell functions and how mesenchymal stem cell maturation is regulated - in essence providing invaluable information about how fat and bone cells are formed in the body.