An investigation into the role and regulation of BACE1.

细胞是所有已知生物体的基本单位，而人类由许多不同的高度专业化的细胞类型组成。为了正常运作，细胞需要与环境和邻近的细胞进行交流。这需要通过细胞膜传递信息，从而将细胞内部与外部环境分开。实现这一点的一个主要机制是通过激活位于细胞表面的蛋白质，即所谓的受体。连接配体(钥匙)开关在受体(锁)上，导致信号级联，导致细胞反应，包括生长、分化和死亡。例如，胰岛素受体识别荷尔蒙配体胰岛素并对其做出反应。对于细胞来说，能够控制它接收的信号是至关重要的。实现这一点的一种方式是通过分子剪刀的作用。这些蛋白质切断了受体的部分，这意味着配体无法附着。这是一个正常的细胞过程，结果是关闭信号，向细胞提供适量和持续的信号。然而，切割太多或太少都会导致错误的沟通，导致发育异常和癌症、痴呆和心脏病等疾病。因此，了解这些分子剪刀是如何工作的，以及它们是如何被调控的，对于了解细胞之间的沟通方式以及这种沟通如何被扭曲导致疾病是至关重要的。在这个项目中，我们将研究其中一种分子剪刀，BACE1。BACE1首先被发现负责产生β-淀粉样蛋白，这些蛋白结合在一起，导致阿尔茨海默病的发展。然而，最近的研究发现，大脑中有70多种不同的蛋白质被BACE1切割。因此，很明显，BACE1蛋白可以在一系列细胞信号的调节中发挥重要作用，从而做出反应。尽管BACE1蛋白存在于人体的大多数细胞中，但到目前为止，研究人员一直专注于大脑。因此，我们计划研究BACE1在内皮细胞中的作用，内皮细胞是人体内发现的一种重要细胞类型。这些细胞负责调节血流，向组织输送营养物质和氧气，并防止感染。在这个项目中，我们的目标是了解BACE1参与的基本细胞功能。为此，我们计划探索以下几个方面：1)我们将使用一种称为质谱学的技术，识别哪些蛋白质与BACE1密切相关，哪些蛋白质被切割。2)我们还将研究激素、血流和低氧等生理刺激如何调节BACE1的活性，以及这如何影响它选择切割哪些蛋白质。3)最后，我们已经证明，降低BACE1的活性可以对内皮细胞产生重大影响。因此，我们将进一步研究BACE1的调控对内皮细胞的生长、血管形成和感知环境等功能的影响，结果将为细胞如何能够调控彼此之间的通讯提供基础信息。这些发现可能会对理解各种细胞类型中的许多细胞过程产生广泛的影响。此外，这项研究有能力揭示对细胞通讯中断的疾病的重要理解。这是潜在的重要知识，可能导致操纵BACE1的作用成为恢复细胞内稳态的一种方式。

The cell is the basic unit of all known living organisms, and humans consist of many different and highly specialised types of cells. To function properly cells, need to communicate with both their environment and neighbouring cells. This requires the passing of information across the cell membrane, which separates the interior of the cell from the outside environment. One main mechanism by which this is achieved is though activation of proteins located in the cell surface, so called receptors. Attaching of a ligand (key) switches on the receptor (lock) which causes a signalling cascade resulting in a cellular response, including growth, differentiation and death. For example, the insulin receptor recognises and responds to the hormone ligand, insulin. It is crucial for cells to be able to control the signals it receives. One way this is achieved is via the actions of molecular scissors. These proteins cut off sections of the receptor, meaning the ligand cannot attach. This is a normal cellular process and results in switching off the signal, providing an appropriate amount and duration of signal to the cell. However, too much or too little cutting leads to mis-communication resulting in developmental abnormalities and diseases including cancer, dementia and heart disease.Therefore, understanding how these molecular scissors work and how they are regulated is fundamental to understanding how cells communicate with each other and how this can be distorted leading to disease.In this project we will study one of these molecular scissors, BACE1. BACE1 was first identified as being responsible for the production of beta-amyloid proteins, which combine, leading to the development of Alzheimer's disease. However, recent studies have identified more than 70 different proteins in the brain which are cut by BACE1. So, it is becoming apparent that the BACE1 protein could play a major role in the regulation of a range of cell signals and therefore responses.Despite BACE1 protein being found in most of the cells in the body, researchers have up until now have focused on the brain. So, we plan to examine the role of BACE1 in endothelial cells, an important cell type found throughout the body. These cells are responsible for regulating blood flow, nutrient and oxygen delivery to tissues and preventing infections.In this project we aim to understand what basic cellular functions BACE1 is involved with. To do this we plan to explore the following aspects:1) We will identify what proteins come in close proximity of BACE1 and of those which are cut, using a technique known as mass spectrometry. 2) We will also investigate how physiological stimuli such as hormones, blood flow and low oxygen regulate BACE1 activity and how this affects which proteins it selects to cut.3) Finally, we have shown that reducing the activity of BACE1 can have major effects on endothelial cells. Therefore, we will further examine what effect the regulation of BACE1 has on endothelial cell functions including growth, formation of blood vessels and sensing the environment.The results will provide fundamental information on how cells are able to regulate communication with each other. These findings could have wide ranging impact for the understanding of many cell processes in a range of cell types. Furthermore, this study has the capacity to uncover important understanding for diseases where cell communication is disrupted. This is potentially important knowledge which could lead to manipulation of BACE1 actions being a way to restore cell homeostasis.