MMP activation during xenopus development

动物已经进化出多种方式，从受精卵成长为具有生殖能力的成体。使用了许多发展战略和方法，但有几个常量。在这些常量中，需要细胞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，这些事件在一定程度上是由细胞外的蛋白质--细胞外基质(ECM)调节的。ECM已经被承认了几十年，但直到最近才清楚地认识到它的重要性。细胞外基质可以影响细胞之间的通信方式，因此细胞外基质的退化或重塑将影响这种细胞间的通信。这些变化和ECM的重塑已经在癌症等疾病中观察到，在这些疾病中，发现了能够改变ECM的分泌酶(基质金属蛋白酶，MMPs)。众所周知，基质金属蛋白在发展中发挥着重要作用，它们适当地调节细胞外基质的结构。由于MMP可以产生深远的影响，它们的活动受到多种方式的监管。大多数MMPs在细胞外以非活性形式分泌，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。耐人寻味的(和直觉相反的)MT-MMPs与分泌的抑制物TIMPs(它们的抑制物)一起作用于激活其他MMPs。这一激活过程被微妙地平衡，因为过量的TIMP分子会抑制所有MT-MMPs，从而停止激活过程。MMPs、MT-MMPs和TIMPs分别具有重要的发育功能。然而，关于它们如何相互作用以适当调节细胞外基质在发育过程中的重塑，人们知之甚少。本研究提案使用青蛙作为发育模型，可以用来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活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.