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.

该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的细胞组成。要正常运行细胞，需要与它们的环境和相邻的细胞进行通信。这需要信息通过细胞膜的传递，这将细胞的内部与外部环境区分开。实现这一目标的一种主要机制是激活位于细胞表面的蛋白质，所谓的受体。配体（钥匙）的附着在受体（锁）上的连接会导致信号传导级联反应，导致细胞反应，包括生长，分化和死亡。例如，胰岛素受体识别并应对激素配体胰岛素。对于细胞控制其接收的信号至关重要。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，导致关闭信号，为单元提供适当的信号量和持续时间。然而，过多或太少的切割导致通信不良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如何受到调节是为了理解细胞对彼此相互交流以及如何扭曲这些项目的疾病的基础。 Bace1首先被确定为负责β-淀粉样蛋白的产生，该蛋白结合起来，导致阿尔茨海默氏病的发展。但是，最近的研究已经确定了大脑中70多种由BACE1切割的蛋白质。因此，很明显，BACE1蛋白可以在调节一系列细胞信号中起主要作用，因此可以发挥反应。尽管在体内的大多数细胞中都发现了dite Bace1蛋白，但研究人员直到现在一直集中在大脑上。因此，我们计划检查BACE1在内皮细胞中的作用，内皮细胞是整个体内发现的重要细胞类型。这些细胞负责调节血流，营养和氧气向组织的递送并预防感染。在该项目中，我们旨在了解BACE1涉及哪些基本细胞功能。为此，我们计划探索以下方面：1）我们将使用一种称为质谱法的技术来确定哪些蛋白质与Bace1的近距离和被切割的蛋白质相近。 2）我们还将研究生理刺激，例如激素，血流和低氧气调节BACE1活性，以及这如何影响其选择要切割的蛋白质。3）最后，我们表明，减少Bace1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对内皮细胞功能的调节对包括生长，血管形成和感测环境的影响。结果将提供有关细胞如何能够相互调节通信的基本信息。这些发现可能会对理解一系列细胞类型的许多细胞过程产生广泛的影响。此外，这项研究有能力发现对破坏细胞通信的疾病的重要理解。这是潜在的重要知识，可能导致操纵BACE1动作是恢复细胞稳态的一种方式。