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An investigation into the role and regulation of BACE1.

BACE1 的作用和调节的研究。

基本信息

批准号：
BB/V014358/1
负责人：
Paul Meakin
金额：
$ 73.61万
依托单位：
University of Leeds
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2022
资助国家：
英国
起止时间：
2022 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FV014358%2F1
关键词：
investigation into role regulation BACE1.

项目摘要

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.

细胞是所有已知生物体的基本单位，人类由许多不同的高度特化的细胞组成。为了正常工作，细胞需要与环境和邻近细胞进行沟通。这需要通过细胞膜传递信息，细胞膜将细胞内部与外部环境分开。实现这一目标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。配体的附着（钥匙）打开受体（锁），引起信号级联，导致细胞反应，包括生长、分化和死亡。例如，胰岛素受体识别并对激素配体胰岛素作出反应。细胞能够控制接收到的信号是至关重要的。实现这一目标的一种方法是通过分子剪刀的作用。这些蛋白质切断受体的部分，这意味着配体不能附着。这是一个正常的细胞过程，其结果是关闭信号，为细胞提供适当数量和持续时间的信号。然而，过多或过少的切割都会导致沟通不畅，从而导致发育异常和疾病，包括癌症、痴呆和心脏病。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节的，对于理解细胞如何相互交流以及这种交流如何被扭曲导致疾病是至关重要的。在这个项目中，我们将研究其中的一个分子剪刀BACE1。BACE1最初被确定为负责β -淀粉样蛋白的产生，这两种蛋白结合在一起，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，BACE1蛋白在调节一系列细胞信号和应答中发挥重要作用的可能性越来越明显。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，这是一种遍布全身的重要细胞类型。这些细胞负责调节血液流动、向组织输送营养和氧气以及预防感染。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法的技术，确定哪些蛋白质与BACE1接近，哪些蛋白质被切割。2)我们还将研究生理刺激（如激素、血流和低氧）如何调节BACE1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调控对内皮细胞生长、血管形成和环境感知等功能的影响。这一结果将为细胞如何调节彼此之间的交流提供基础信息。这些发现可能对理解一系列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。这是一个潜在的重要知识，它可能导致BACE1行为的操纵成为恢复细胞稳态的一种方式。