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Genetic basis of intrinsic and extrinsic contributions to the establishment of muscle pattern in the developing limb

肢体发育中肌肉模式建立的内在和外在贡献的遗传基础

基本信息

批准号：
BB/D521865/1
负责人：
Baljinder Mankoo
金额：
$ 32.04万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2006
资助国家：
英国
起止时间：
2006 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FD521865%2F1
关键词：
Genetic basis intrinsic extrinsic contributions

项目摘要

If you open a book showing the inside of the human body one of the most striking things is how the tissues and organs are present in the right place and at the correct shape and size. One of the questions that we want to find the answer to is: how do tissues and organs develop in this way? We know that this is controlled to an extent by genes, because mutations, which cause genes to be defective, can make tissues and organs to develop abnormally. We are looking at how the muscles of the body develop in the embryo. The human body has about 650 muscles, some muscles are very large (in the leg), others are very small (in the eye). We know that each of the 40 muscles in the arm has a particular place, and it is connected by tendons to particular places on bones at each end. Because this is the same in different people, we can give a name to each muscle. The question we ask is: how does this happen? For the muscles of the arms and legs this is particularly interesting as these muscles have the strange behaviour in that they grow from muscle cells that move into the arm or leg as the embryo develops. How do these muscles know where to go in the limb and make a particular muscle, why don¿t they get all mixed up and make a jumbled muscle, and how do they make the specific attachments to bones? There are different possible solutions to this problem. One way might be that the muscle cells are programmed to know where they have to go. This is like going for a car drive and you know where you will be going and the route you will take before you start. Alternatively, muscle cells may have no clue where they are going but just follow the directions they are given. This is like a train that can go forwards, but where it goes depends on the train tracks and signals being set correctly by someone else. Scientists think that the train on the tracks model probably is a better explanation of how muscle cells move to their correct locations, and cells in the limb give signals to the muscle cells such as: move here; don¿t go there; keep moving; stop now; make a muscle now. But this is not 100 per cent certain. We wish to do a project to look into this and see if we can find some answers. We shall use a mutant mouse that has a mutation in a gene that makes a protein that switches on other genes. It is what we call a regulator gene. Mice which have a mutation in this regulator gene have very peculiar problems in the way muscles in their arms and legs form. We have noticed that some muscles are completely missing, other muscles form in places that they should not, and some muscles although they are in the right place have split into two muscles. On top of this we have seen that the tendons of the muscles are also abnormal, and many of them are much smaller than normal. We want to find out if these muscle problems are because the muscle cells that make this muscle are defective in their programme (as if some of them cannot read the road map correctly), or is this because the tendon cells and others which may signal to the muscle cells are defective (as if the switches on the rail track have been left in the wrong position, so the train goes in the wrong direction).

如果你打开一本展示人体内部的书，最引人注目的事情之一就是组织和器官是如何以正确的形状和大小出现在正确的位置上的。我们想要找到答案的一个问题是：组织和器官是如何以这种方式发育的？我们知道，这在一定程度上是由基因控制的，因为导致基因缺陷的突变会使组织和器官发育异常。我们正在研究人体肌肉在胚胎时期是如何发育的。人体大约有650块肌肉，有些肌肉很大（在腿上），有些肌肉很小（在眼睛上）。我们知道手臂上的40块肌肉每一块都有一个特定的位置，它们通过肌腱连接到骨头两端的特定位置。因为这在不同的人身上都是一样的，我们可以给每一块肌肉起一个名字。我们要问的问题是：这是怎么发生的？对于胳膊和腿的肌肉来说，这是特别有趣的，因为这些肌肉有一种奇怪的行为，它们是从肌肉细胞生长出来的，随着胚胎的发育，肌肉细胞会进入胳膊或腿。这些肌肉是如何知道肢体的位置并形成特定的肌肉的，为什么它们不会混合在一起形成混乱的肌肉，以及它们是如何形成特定的附着在骨头上的？这个问题有不同的可能解决方案。一种可能是，肌肉细胞被编程为知道它们应该去哪里。这就像开车去兜风，你知道你要去哪里，你要走的路线在你开始之前。另一种情况是，肌肉细胞可能不知道它们要去哪里，只是跟着它们被赋予的方向走。这就像一列可以前进的火车，但它的去向取决于火车的轨道和其他人设置的正确信号。科学家们认为，轨道上的火车模型可能更好地解释了肌肉细胞如何移动到正确的位置，以及肢体中的细胞如何向肌肉细胞发出信号，比如：移动到这里；不要去那里；继续前进;现在停止;现在练练肌肉。但这并非百分之百确定。我们希望做一个项目来研究这个问题，看看我们是否能找到一些答案。我们将使用一只突变的老鼠，它的一个基因发生了突变，产生了一种蛋白质，这种蛋白质可以开启其他基因。这就是我们所说的调节基因。这种调节基因发生突变的老鼠在手臂和腿部肌肉形成的方式上出现了非常特殊的问题。我们注意到，有些肌肉完全消失了，有些肌肉在不应该出现的地方形成，有些肌肉虽然在正确的位置，但却分裂成两块肌肉。除此之外，我们还看到肌肉的肌腱也不正常，其中许多比正常的肌腱小得多。我们想弄清楚这些肌肉问题是由于构成肌肉的肌肉细胞在它们的程序中有缺陷（就好像有些肌肉细胞不能正确地阅读路线图），还是因为肌腱细胞和其他可能向肌肉细胞发出信号的细胞有缺陷（就好像铁轨上的开关被放在错误的位置，所以火车行驶在错误的方向上）。