Dynamic Regulation of the Cell Surface Proteome

细胞表面蛋白质组的动态调控

• 批准号: RGPIN-2016-04371
• 负责人: Antonescu, Costin
• 金额: $ 2.26万
• 依托单位: Ryerson University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=615019
• 关键词: Dynamic; Regulation; Cell; Surface; Proteome

Each living cell must interact with its surroundings through the molecules present on its outer surface. Proteins are an important type of molecule found on every cell’s surface. These cell surface proteins are essential for many cellular functions including the uptake of nutrients such as sugar and vitamins from a cell's surroundings, for attachment to other cells or tissues and for sensing messages from other cells or organisms (e.g. through hormones). The proteins found on a cell’s surface work as part of cellular processes that can require a lot of a cell’s energy resources, for example in cell movement or migration. Much like household income and expenditures should be balanced, a cell’s energetically demanding processes have to be tightly controlled so that energy expenditure is kept in line with a cell’s needs and abilities. The long-term goal of our research is to understand how a cell controls the hundreds and perhaps thousands of different types of proteins at its surface to allow that cell to survive and adapt to changing environments. In particular, we seek to understand how a cell senses its own energetic state, and uses this information to control or limit energy-demanding processes that the cell surface. We have recently found that cells have a specific adaptive mechanism to shut down one of their most energy-demanding processes when they sense that they do not have enough energy: cell movement and migration. The key molecular sensor within a cell is a protein called AMP-activated protein kinase (or AMPK), which functions like a cell's fuel gauge; AMPK becomes activated when energy stores are depleted, and works to restore a cell’s energy stores. We propose to undertake research aiming to understand how human cells control their surface proteins (in particular those that govern cell migration and attachment) in response to the availability of their own energy stores and fuel production. We will focus on the study of a family of cell surface proteins that control cell migration that are called integrins, and how these are controlled by energy state and AMPK. To do this, we will use advanced forms of microscopy along with tools to “tag” a number of proteins such as integrins with a fluorescent label, which will allow us to “see” them in living cells. Understanding how cell metabolism controls the proteins at the surface of a cell will provide valuable information about a fundamental biological process taking place in virtually every cell in the human body to ensure survival. Through additional experiments, we also plan to reveal how AMPK controls the function of kidney cells, a type of cell that is particularly prone to “energy shortage”. Hence, these experiments will provide new information about kidney function and will provide unprecedented new knowledge about an important, fundamental, yet unexplored phenomenon of biology that controls the behavior of every cell in the human body.

每个活细胞必须通过其外表面的分子与其周围环境相互作用。蛋白质是每个细胞表面发现的一种重要分子。这些细胞表面蛋白对于许多细胞功能至关重要，包括从细胞周围吸收糖和维生素等营养物质、附着到其他细胞或组织以及感知来自其他细胞或生物体的信息（例如通过激素）。细胞表面发现的蛋白质是细胞过程的一部分，可能需要大量细胞的能量资源，例如细胞运动或迁移。就像家庭收入和支出应该平衡一样，细胞的能量消耗过程也必须受到严格控制，以使能量支出与细胞的需求和能力保持一致。 我们研究的长期目标是了解细胞如何控制其表面的数百甚至数千种不同类型的蛋白质，以使细胞能够生存并适应不断变化的环境。特别是，我们试图了解细胞如何感知自身的能量状态，并利用这些信息来控制或限制细胞表面的耗能过程。我们最近发现，细胞有一种特定的适应机制，当它们感觉到自己没有足够的能量时，会关闭最需要能量的过程之一：细胞运动和迁移。细胞内的关键分子传感器是一种称为 AMP 激活蛋白激酶（或 AMPK）的蛋白质，其功能类似于细胞的电量计；当能量储存耗尽时，AMPK 就会被激活，并致力于恢复细胞的能量储存。 我们建议进行研究，旨在了解人类细胞如何控制其表面蛋白（特别是那些控制细胞迁移和附着的蛋白），以响应其自身能量储存和燃料生产的可用性。我们将重点研究控制细胞迁移的细胞表面蛋白家族（称为整合素），以及它们如何受能量状态和 AMPK 控制。为此，我们将使用先进的显微镜和工具来“标记”许多蛋白质，例如带有荧光标记的整合素，这将使我们能够在活细胞中“看到”它们。 了解细胞代谢如何控制细胞表面的蛋白质将为人体几乎每个细胞中发生的基本生物过程提供有价值的信息，以确保生存。通过额外的实验，我们还计划揭示 AMPK 如何控制肾细胞的功能，肾细胞是一种特别容易出现“能量短缺”的细胞。因此，这些实验将提供有关肾功能的新信息，并将提供有关控制人体每个细胞行为的重要、基本但尚未探索的生物学现象的前所未有的新知识。