CMB&RM Seminar: David Beech "Piezo1 mechano-sensor in vascular physiology and disease"
|Starts:||13:00 29 Mar 2019|
|Ends:||14:00 29 Mar 2019|
|What is it:||Seminar|
|Organiser:||Faculty of Biology, Medicine and Health|
|Who is it for:||University staff, Current University students|
In mammals the sensing of blood flow is pivotal for embryonic maturation and adult physiology and disease. How this sensing occurs has been surprisingly difficult to decipher. We have revealed how calcium-permeable non-selective cationic channels formed by Piezo1 proteins assemble to act as sensors of blood flow and determinants of vascular structure in murine development and adult physiology (Li et al 2014 Nature 515, 279-). Conditional deletion has been necessary for detailed studies in the adult where we found endothelial Piezo1 was not essential for life but necessary for blood pressure determination during whole body physical exercise (Rode et al 2017 Nature Comms 8, 350-). We suggested that it behaves as an exercise sensor (Beech 2017 J Physiol 596, 979-). In both embryo and adult we found compelling evidence for endothelial Piezo1 channels as direct sensors of force, yet exactly how they enable sensing of this force – and thus of blood flow - remains unclear. Intriguingly, Piezo1 channels present a dichotomy for the endothelium in conferring both vasodilator and vasoconstrictor capabilities, the relative importance of which may depend on context (Rode et al 2017; Evans et al 2018 Br J Pharmacol 175, 1744-). Small-molecule activation of Piezo1 channels has been discovered in the form of Yoda1 and our studies have started to show the tight chemical requirements for this pharmacological effect, yet there was sufficient flexibility for us to discovery a competitive antagonist of Yoda1 which we refer to as Dooku1 (Evans et al 2018). Disease-causing mutations in human PIEZO1 have been linked to Generalized Lymphatic Dysplasia, suggesting importance in human endothelium. Our studies of tissues from patients are also suggesting relevance to human physiology and disease (Morley et al 2018 Mol Hum Reprod 24, 510-). While there might be potential for novel therapeutics targeted to Piezo1 it will be necessary to take account of the broad roles of Piezo1 in various cell and tissue types (Beech & Xiao 2018 J Physiol 596, 965-; Beech 2019 Cell Calcium 77, 77-78). Supported by grants from the Medical Research Council UK, Wellcome Trust and British Heart Foundation.
Organisation: Leeds Institute of Cardiovascular and Metabolic Medicine
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