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Modulation of Piezo1 by lipids and synthetic small-molecules

Hyman, Adam James (2018) Modulation of Piezo1 by lipids and synthetic small-molecules. PhD thesis, University of Leeds.

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Hyman_AJ_BiomedicalSciences_PhD_2018.pdf - Final eThesis - complete (pdf)
Restricted until 1 July 2023.

Abstract

Regulation of Ca2+ entry plays important roles in cardiovascular physiology and pathophysiology. Understanding how these processes are altered in pathophysiological states and designing drugs to target Ca2+ entry into cells may provide avenues for developing new therapeutic strategies for cardiovascular disease, such as atherosclerosis. The overall aim of this study was to identify mechanisms of regulating the Ca2+ permeable ion channel Piezo1 by lipids and synthesised small molecules. Piezo1 proteins form mechanosensitive non-selective cation channels that have been shown to have important roles in vascular development, endothelial shear stress sensing and regulation of vascular tone. In this study, the impact of cholesterol on Piezo1 was investigated because it is a risk factor in cardiovascular diseases and an important membrane constituent. Piezo1-mediated calcium entry was inhibited by addition and depletion of cholesterol from cell membranes. Cholesterol interaction sites were found within the structure of Piezo1. Mutating these interaction sites reduced Piezo1 sensitivity to cholesterol addition. The data suggest previously unrecognised mechanisms of Piezo1 regulation by cholesterol through interaction sites. Sphingolipids form a diverse class of signalling lipids. Production of sphingolipids can occur by activation of sphingomyelinase which often occurs in response to inflammatory stimuli, infection or cell stress. Here sphingomyelinase activity is shown to potentiate activation of endothelial Piezo1 by Yoda1, a chemical activator of Piezo1. The mechanism of potentiation occurred through production of sphingosine and subsequent inhibition of protein kinase C, activation of phospholipase C and activation of protein kinase D. These data suggest endothelial Piezo1 activity may be modulated by inflammatory mediators which may have major roles in cardiovascular disease. Targeting Piezo1 pharmacologically may provide treatments for diseases in the future. Modifying the activator of Piezo1, Yoda1, revealed a novel activator of Piezo1 with desirable characteristics for compound development. In summary, this research developed new knowledge and hypotheses about modulation of Piezo1 by lipids and novel small-molecules which may provide better understanding of cardiovascular disease and new treatment strategies.

Item Type: Thesis (PhD)
Keywords: Piezo1, Lipids, Calcium Signalling, Cardiovascular Disease
Academic Units: The University of Leeds > Faculty of Biological Sciences (Leeds)
Depositing User: Mr Adam Hyman
Date Deposited: 20 Jun 2018 11:47
Last Modified: 20 Jun 2018 11:47
URI: http://etheses.whiterose.ac.uk/id/eprint/20266

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