The role of Crim1, a novel TGFb superfamily modulator, in early vertebrate patterning, vascular and renal development.

转化生长因子β超家族是一大类分泌型生长因子，在脑、骨骼、心脏、肾脏、眼睛、牙齿和四肢等组织的正常发育过程中发挥着不同的作用。超家族中的一组，骨形态发生蛋白(BMPs)，正被用于临床试验，以帮助骨折后的骨骼再生。这些分子也具有临床意义，因为这个家族中的生长因子也可能是有害的，它们的过度表达会导致肾纤维化和白内障等疾病。这些生长因子的活性受许多其他蛋白质的调节，包括结合和失活它们的蛋白质拮抗剂。因此，通过了解这些拮抗剂，我们有可能找到改变转化生长因子β超家族活性的新方法。我们之前已经发现了一种新的蛋白Crim1，现在我们已经证明它可以与转化生长因子超家族成员结合，并可以减少他们的分泌。我们认为，Crim1通过调节TGFβ超家族，在中枢神经系统的模式形成、血管和肾脏的发育中发挥作用。在这笔拨款中，我们将调查CRIM1的干扰对这些器官系统的影响，并找出它正在影响TGFbeta超家族的哪些成员导致这些影响。为了做到这一点，我们将敲除斑马鱼的基因，并描述在该基因被破坏的小鼠品系中发现的缺陷。这对于在一些临床条件下开发激活或灭活这些生长因子的新方法可能是重要的。

The transforming growth factor (TGF) beta superfamily is a large group of secreted growth factors who play many different roles in normal development of tissues such as the brain, skeleton, heart, kidney, eyes, teeth and limbs. One of the groups within the superfamily, the bone morphogenetic proteins (BMPs), are being used in clinical trials to assist in regrowing bones after fracture. These molecules are also of interest for clinical reasons as growth factors within this family can also be deleterious, with their overexpression leading to conditions such as renal fibrosis and cataract. The activity of these growth factors is regulated by many other proteins, including protein antagonists which bind and inactivate them. It is therefore possible that by understanding these antagonists, we can find new ways of altering TGF beta superfamily activity. We have previously identified a novel protein, Crim1, which we have now shown can bind to TGF superfamily members and can reduce their secretion. We believe that Crim1 plays a role in the patterning of the central nervous system, the development of the blood vessels and the kidneys by regulating the TGFbeta superfamily. In this grant we will be investigating what the effect of disruption to Crim1 is on these organ systems and working out which members of the TGFbeta superfamily it is affecting to cause these effects. To do this, we will knock out the gene in zebrafish and characterise the defects found in a mouse line in which the gene has been disrupted. This may be important in developing new ways of activating or inactiviating these growth factors in a number of clinical conditions.