MMP activation during xenopus development

动物从受精卵到成年生殖体的过程中进化出了许多种方式。使用了许多发展战略和方法，但有几个常数。在这些常数中，需要细胞与细胞之间的通信和相互作用。这些相互作用允许重要的信号事件在发育过程中的正确时间和地点发生。有趣的是，这些事件部分是由细胞外发现的蛋白质-细胞外基质（ECM）调节的。企业内容管理几十年来一直得到认可，但直到最近才清楚地认识到其重要性。ECM可以影响细胞如何相互通信，因此ECM的降解或重塑将影响这种细胞间通信。已经在疾病如癌症中观察到ECM的这些变化和重塑，其中鉴定出改变ECM的分泌酶（基质金属蛋白酶，MMP）。现在已知MMPs在发育中发挥重要作用，其中它们适当地调节ECM的结构。由于MMPs可以产生深远的影响，它们的活性以多种方式受到调节。大多数MMP以非活性形式分泌到细胞外，并在需要时被激活。MMPs通常被称为MT-MMPs的其他细胞表面MMPs激活。有趣的是（与直觉相反）MT-MMPs与分泌的抑制剂TIMP（它们的抑制剂）一起激活其他MMPs。这种激活过程是微妙的平衡，因为过量的TIMP分子会抑制所有MT-MMP，从而停止激活过程。MMPs、MT-MMP和TIMPs各自具有重要的发育功能。然而，很少有人知道它们如何相互作用，以适当地调节ECM在发育过程中的重塑。 这项研究计划使用青蛙作为发育模型，可以分析这些分子的功能和相互作用。通过了解它们的作用以及它们在生物体发育过程中的作用，我们可以更好地了解在正常和异常胚胎发生中发挥作用的潜在机制。

Animals have evolved numerous ways to grow from a fertilized egg to a reproductive adult. Many developmental strategies and approaches are used, but there are several constants. Among these constants is the need for cell-to-cell communication and interactions. These interactions allow for important signalling events to occur at the correct time and place during development. Interestingly these events in part are regulated by proteins found outside of cells - the extracellular matrix (ECM). The ECM has been recognized for decades, but it is only recently that its importance is clearly understood. The ECM can influence how cells communicate with each other, and so the degradation or remodelling of the ECM will affect this cell-cell communication. These changes and remodelling of the ECM have been observed in diseases such as cancer where secreted enzymes (matrix metalloproteinases, MMPs) were identified that changed the ECM. MMPs are now known to play important roles in development, where they appropriately regulate the structure of the ECM. As MMPs can have profound impacts, their activity is regulated in a number of ways. Most MMPs are secreted outside of cells in an inactive form and are activated when needed. MMPs are often activated by other cell-surface MMPs called MT-MMPs. Intriguingly (and counter intuitively) MT-MMPs work with secreted inhibitors, TIMPs (their inhibitors) to activate other MMPs. This activation process is delicately balanced as an excess of TIMP molecules would inhibit all MT-MMPs and thus stop the activation process. MMPs, MT-MMP and TIMPs individually have important developmental functions. However, very little is known about how they interact with each other to appropriately regulate the remodelling of the ECM during development.  This research proposal uses frog as a developmental model with which the functions and interactions of these molecules can be assayed. By understanding their role and how they act during the development of a living organism we can then better understand the underlying mechanisms that play a role in normal and abnormal embryogenesis.