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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，人类由许多不同且高度专业化的细胞组成。为了正常运作的细胞，需要与他们的环境和相邻的细胞进行通信。这需要信息穿过细胞膜传递，细胞膜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。配体（钥匙）的连接打开受体（锁），这引起信号级联，导致细胞反应，包括生长、分化和死亡。例如，胰岛素受体识别并响应激素配体胰岛素。细胞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法是通过分子剪刀的作用。这些蛋白质切断了受体的部分，这意味着配体不能附着。这是一个正常的细胞过程，并导致关闭信号，向细胞提供适当数量和持续时间的信号。然而，太多或太少的切割会导致错误的沟通，从而导致发育异常和疾病，包括癌症，痴呆症和心脏病。因此，了解这些分子剪刀如何工作以及它们是如何调节的对于了解细胞如何相互交流以及如何扭曲导致疾病至关重要。在这个项目中，我们将研究这些分子剪刀之一，BACE 1。BACE 1首先被鉴定为负责β-淀粉样蛋白的产生，β-淀粉样蛋白联合收割机，导致阿尔茨海默病的发展。然而，最近的研究已经确定了大脑中被BACE 1切割的70多种不同蛋白质。因此，BACE 1蛋白在调节一系列细胞信号和反应中发挥重要作用变得越来越明显。尽管BACE 1蛋白存在于体内大多数细胞中，但研究人员迄今为止一直专注于大脑。因此，我们计划研究BACE 1在内皮细胞中的作用，内皮细胞是全身发现的一种重要细胞类型。这些细胞负责调节血液流动，营养和氧气输送到组织和预防感染。在这个项目中，我们的目标是了解BACE 1参与的基本细胞功能。为了做到这一点，我们计划探索以下几个方面：1）我们将使用一种称为质谱的技术来鉴定哪些蛋白质与BACE 1非常接近，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BACE 1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BACE 1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BACE 1的调节对内皮细胞功能（包括生长、血管形成和感知环境）的影响，结果将为细胞如何能够调节彼此之间的通信提供基础信息。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。这是潜在的重要知识，可能导致BACE 1作用的操纵成为恢复细胞稳态的一种方式。