PAR-1, polarity and Wnt signalling in early vertebrate embryos

我们有充分的理由希望，在未来，使用与胚胎正常发育期间产生身体结构相同的天然化学物质，有可能再生身体受损或患病的部位。为了使这成为可能，首先有必要详细了解这些被称为形态原的化学物质是如何起作用的。这个项目建议分析一种被称为Wnt的特殊形态。Wnt被用于(a)触发特定基因的开启，这些基因构成了身体的头部和前端；(b)指导胚胎内细胞的运动，使其长而窄（而不是短而圆）。这两个过程一个接一个发生得很快，人们还不清楚参与这两个过程的许多细胞如何能够对同一个Wnt信号做出不同的反应。我们一直在研究另一种蛋白质PAR-1，它可能有助于我们理解不同的Wnt反应。PAR-1是一种存在于细胞内的蛋白质，它使细胞的一端与另一端不同。一层这样的细胞（称为上皮细胞）。例如，你的肠道或肾脏的内壁)因此可以有一个表面与另一个非常不同（即具有上皮极性）。我们认为到达一个表面的Wnt可能与到达另一个表面的Wnt表现不同。PAR-1可能在这方面很重要，因为不同版本的PAR-1蛋白对Wnt的反应不同，并且可能定位于上皮的相反表面。为了验证这一点，我们将(1)检查不同版本的PAR-1是否确实定位到不同的表面，如果是这样，PAR-1结构的哪些部分能够实现这种差异定位；(2)确定上述wnt诱导的细胞运动是否受到PAR-1去除的影响，因为上皮极性被破坏；(3)通过测试一些候选蛋白质和筛选其他蛋白质目标，找出PAR-1（一种修饰其他蛋白质的酶）的实际作用（即它修饰哪些其他蛋白质）。这些实验将有助于解决问题。接线图吗?对胚胎中的细胞进行调节，并最终使细胞能够被操纵以获得治疗结果。

There are good reasons to hope that in the future it will be possible to regenerate damaged or diseased parts of the body using the same natural chemicals that generate the structure of the body during normal development of the embryo. For this to be a possibility, it is first essential to get a detailed understanding of how those chemicals, known as morphogens, do their job. This project proposes to analyse a particular morphogen known as Wnt. Wnt is used, among other things, (a) to trigger the switching on of particular genes that make the head and front end of the body and (b) to direct the movements of cells within the embryo so that it is long and narrow (rather than short and round). These two processes happen quite quickly after one another and it is not properly understood how the many cells involved in both processes are able to respond differently to the same Wnt signal. We have been studying another protein, PAR-1, that may help us understand the different Wnt responses. PAR-1 is a protein that exists within cells that makes one end of a cell different from the other. A layer of such cells (known as ?epithelia? e.g. the lining of your gut or kidney) can therefore have one surface be very different from the other (i.e. have epithelial polarity). We believe that Wnt arriving on one surface may act differently from Wnt arriving at the other surface. PAR-1 may be important in this because different versions of the PAR-1 protein react differently to Wnt and may be localised to opposite surfaces of epithelia. To test this, we will (1) check to see if different versions of PAR-1 are indeed localised to the different surfaces, and if so which parts of the structure of PAR-1 enable this differential localisation; (2) determine whether the Wnt-induced cell movements mentioned above, which we know are affected by PAR-1 removal, are affected because the epithelial polarity is disrupted; and (3) find out what PAR-1, which is an enzyme that modifies other proteins, actually does (i.e. which other proteins it modifies), both by testing some candidate proteins and screening for other protein targets. These experiments will help work out the ?wiring diagram? for cell regulation in embryos and ultimately enable cells to be manipulated for therapeutic outcomes.