Award details

An investigation into the role and regulation of BACE1.

Reference	BB/V014358/1
Principal Investigator / Supervisor	Dr Paul Meakin
Co-Investigators / Co-Supervisors
Institution	University of Leeds
Department	School of Medicine
Funding type	Research
Value (£)	577,665
Status	Current
Type	Research Grant
Start date	01/04/2022
End date	31/03/2025
Duration	36 months

Abstract

Receptor ectodomain shedding is a fundamental and tightly regulated process in cell biology. It is a rapid and irreversible post-translational modification, which can have either profound positive or negative effects on cellular signalling and whole-body homeostasis. The enzymes responsible, referred to as sheddases, regulate the levels and function of hundreds of membrane proteins. As such these enzymes act as switches to regulate diverse processes including signalling and cell adhesion. Additionally, dysregulation of ectodomain shedding is associated with a wide range of pathologies, including autoimmune and cardiovascular diseases, neurodegeneration, infection and cancer. Therefore, understanding the function and regulation of these sheddases is extremely important for cell physiology and pathology. BACE1 is one of only a handful of sheddase enzymes and is sensitive to a number of physiological stimuli, including hypoxia, nutrient levels and blood flow. Therefore, we hypothesise that BACE1 is a stress-sensing sheddase and acts to regulate many cellular responses. To test this hypothesis, we will establish the BACE1 interactome and identify novel substrates using multiple unbiased proteomic approaches. This will significantly develop our understanding of BACE1 and the cellular process it is involved with. To explore the mechanism(s) involved we will perform post translational modification mapping and cellular imaging to establish how physiological stimuli can affect BACE1 activity, cellular localisation and substrate selection. Finally, we will determine the effect of BACE1 post translational modifications on cellular physiology including cell signalling and metabolism, blood vessel formation and mechanosensing. This multi-disciplinary project will lead to new insights in the role and regulation of BACE1. This project will establish a role for BACE1 in normal physiology and could lead to targeting its regulation being a novel means to maintain health.

Summary

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.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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