Role of MT1-matrix metalloproteinase in regulating cell signalling and cell invasion.

MT1-基质金属蛋白酶在调节细胞信号传导和细胞侵袭中的作用。

• 批准号: RGPIN-2018-06665
• 负责人: Damjanovski, Sashko
• 金额: $ 2.33万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=745670
• 关键词: Role; MT1; matrix; metalloproteinase; regulating

Multicellular organisms are composed of trillions of cells held together by secreted proteins called the ECM. However, cells must move, as cell movement is fundamental to embryogenesis. Whether it is the global movements of many cells that shape our entire body plan, or the complicated folding of tissues to form a heart, or the extension of nerves from the central nervous system to innervate a muscle, the movement of groups of cells, individual cells, or even parts of cells, is essential. Cell movement requires the coordination of many biological events. The cells must be signalled when and where to go (get up, move in this direction), and then manifest these signals into the proper cellular machinery needed to facilitate movement. Cell movement involves changes in shape, as the cell pushes out membrane protrusions in a given direction, but movement may also require the passage through the ECM barrier. This passage requires the cells to remodel the ECM in a process termed invasion. Thus, movement must coordinate changes in cell shape, with invasion requiring the additional step of ECM remodelling. During embryogenesis cells elegantly communicate with each other to coordinate which cells move. Such cell movement is rare in adults, but does occur during wound healing, immune responses, pregnancy, and is problematic in disease, where unregulated movement by cells causes problems. The central focus of my research program is to understand how cells interpret extracellular signals to coordinate changes in cell shape and their ability to degrade the ECM. The central player is an enzyme called membrane type 1 matrix metalloproteinase (MT1-MMP), a member of the enzyme family responsible for remodelling the ECM. As with cell movement, these enzymes play important roles during development and disease, but are relatively quiet in adult tissues. MT1-MMP is uniquely special. It is the only family member that is absolutely required during development. And it has a structure whereby it sits on the membrane of a cell. Here it can both remodel the ECM but, as importantly, it can bind to signalling molecule outside of the cell and transmit these signals into the cell to alter the migration machinery. Also, MT1-MMP can bind dozens of external molecules, and turn on several intracellular processes. We aim to see how different external molecules bind to MT1-MMP to trigger different movement mechanisms (to send out a cell protrusion, or to degrade the local ECM etc). While cell movements are critical during embryogenesis, the numerous cell types found in an embryo make it difficult to examine MT1-MMP signals in individual cells. Thus, we will use cells grown in culture; cells that have MT1-MMP, lack MT1-MMP, or that have mutated MT1-MMP that cannot signal into the cell. These cells will be used to investigate the roles played by MT1-MMP in coordinating external signals to regulate cell movement events that are fundamental to embryogenesis.

多细胞生物体由数万亿个细胞组成，这些细胞通过称为ECM的分泌蛋白结合在一起。然而，细胞必须移动，因为细胞移动是胚胎发生的基础。无论是塑造我们整个身体计划的许多细胞的整体运动，还是复杂的组织折叠形成心脏，或者从中枢神经系统延伸神经支配肌肉，细胞群，单个细胞甚至部分细胞的运动都是必不可少的。细胞运动需要许多生物事件的协调。细胞必须被告知何时何地去（起床，向这个方向移动），然后将这些信号显化到促进运动所需的适当细胞机制中。细胞运动涉及形状的变化，因为细胞在给定方向上推出膜突起，但运动也可能需要穿过ECM屏障。这种传代需要细胞在称为侵袭的过程中重塑ECM。因此，运动必须协调细胞形状的变化，入侵需要ECM重塑的额外步骤。在胚胎发育过程中，细胞之间优雅地交流以协调细胞的运动。这种细胞运动在成年人中很少见，但在伤口愈合、免疫反应、怀孕期间确实会发生，并且在疾病中是有问题的，其中细胞的不受调节的运动会导致问题。我的研究计划的中心重点是了解细胞如何解释细胞外信号，以协调细胞形状的变化及其降解ECM的能力。核心参与者是一种称为膜1型基质金属蛋白酶（MT 1-MMP）的酶，它是负责重塑ECM的酶家族的成员。与细胞运动一样，这些酶在发育和疾病过程中发挥重要作用，但在成人组织中相对安静。MT 1-MMP是独一无二的。它是唯一的家庭成员，是绝对需要在发展。它有一个结构，它位于细胞膜上。在这里，它既可以重塑细胞外基质，但同样重要的是，它可以与细胞外的信号分子结合，并将这些信号传递到细胞中以改变迁移机制。此外，MT 1-MMP可以结合数十种外部分子，并打开几个细胞内过程。我们的目标是了解不同的外部分子如何与MT 1-MMP结合以触发不同的运动机制（发出细胞突起，或降解局部ECM等）。虽然细胞运动在胚胎发生过程中至关重要，但胚胎中发现的众多细胞类型使得难以检查单个细胞中的MT 1-MMP信号。因此，我们将使用在培养物中生长的细胞;具有MT 1-MMP、缺乏MT 1-MMP或具有不能向细胞发出信号的突变的MT 1-MMP的细胞。这些细胞将用于研究MT 1-MMP在协调外部信号以调节对胚胎发生至关重要的细胞运动事件中所起的作用。