Exploring extracellular matrix remodelling during lung branching morphogenesis

肺的形成是生存所必需的重要过程。我们的研究重点是了解细胞在肺发育过程中的功能以及这种功能是如何控制的。任何组织中的细胞都被一种叫做细胞外基质的蛋白质“支架”所包围。这种支架并不是一个静态的结构，而是通过移除和添加不同的蛋白质来不断地改变或重塑。重要的是，这种支架具有向细胞发出信号的能力。这种信号可以通过支架和细胞之间的直接相互作用发生，也可以通过支架结合并释放称为生长因子的特定信号蛋白来实现。我以前的工作发现，当支架内的一种蛋白质(称为纤维连接蛋白)发生变化时，肺气道的形成会受到损害，因为呼吸道内的细胞没有适当地分裂(或增殖)。因此，我们建议的研究集中于了解整个支架在肺发育过程中是如何变化的，以及支架的变化是如何改变肺发育的。为了做到这一点，我的实验室将首先检查支架在呼吸道形成期间是如何变化的(即蛋白质是如何沉积或移除的)。我们将从发育中的小鼠身上分离出肺，我们将观察与支架相关的基因的表达，以及这些基因是如何变化的。我们还将使用一种名为Tail的新技术，它可以让我们识别肺内正在发生变化的蛋白质，特别是被酶降解或分解的蛋白质。我们的长期目标将是确定支架的变化如何改变呼吸道的形成。为此，我们将使用一个肺发育模型，其中支架似乎发生了变化，并研究这些变化是如何改变肺发育的。这些研究将使我们能够确定支架，重要的是支架的变化，如何在肺发育过程中控制细胞功能，特别是在呼吸道形成期间。*总的来说，我们的工作将确定新的方法，通过周围的支架或基质来控制发育中的肺的基本细胞功能。重要的是，这与许多不同发育器官中细胞的控制方式有相似之处。因此，除了确定控制肺发育的特定因素外，我们的研究还将解决对许多不同器官发育至关重要的概念。

Formation of the lung is an important process required for survival. Our research is focused on understanding how cells function during lung development and how this function is controlled. Cells within any tissue are surrounded by a “scaffold” of proteins called the extracellular matrix. This scaffold is not a static structure and is constantly being changed or remodelled by removing and adding different proteins. Importantly, this scaffold has the ability to signal to cells. This signalling can occur through direct interaction between the scaffold and the cells, as well as by the scaffold binding to and releasing specific signalling proteins called growth factors. My previous work found that when one of the proteins within the scaffold (called fibronectin) is altered, the formation of the lung airways is impaired because the cells within the airway do not divide (or proliferate) appropriately. Therefore, our proposed studies are focused on understanding how this entire scaffold is changed during lung development and how changes to the scaffold alters lung development.******To do this, my lab will initially examine how the scaffold is changed (i.e. how proteins are deposited or removed) during formation of the airways. Lungs will be isolated from developing mice and we will look at the expression of genes associated with the scaffold and how these genes change. We will also use a new technique, called TAILS, that allows us to identify the proteins within the lung that are being changed, specifically degraded or cleaved by enzymes. Our long term goal will be to determine how changes to the scaffold change airway formation. For this, we will use a model of lung development where the scaffold appears to be changed and examine how these changes alter lung development. These studies will allow us to identify how the scaffold, and importantly, changes to the scaffold, control cell function during lung development, specifically during airway formation.******Overall, our work will identify new ways through which essential cellular functions are controlled in the developing lung by the surrounding scaffold or matrix. Importantly, there is similarity with how cells are controlled in many different developing organs. Thus, in addition to identifying specific factors that control lung development, our studies will address concepts that are important for the development of many different organs.