Understanding vascular mechanical sensitivity. (360G-Wellcome-110044_Z_15_Z)

£1,821,725

My research addresses the multiple poorly understood calcium entry mechanisms in mammalian cells, the purposes the mechanisms serve and whether they can be exploited for therapeutic benefit. Specifically I am interested in the idea that various calcium-permeable channels are expressed in blood vessels in order to sense physical and chemical factors and couple them to remodelling of blood flow. I think the mechanisms are pivotal in major areas of mammalian biology and tractable as routes to new d rugs for the treatment of certain types of cancer, cardiovascular disease and other non-communicable diseases which are prevalent in many societies globally. I recently made the seminal discovery that channels in endothelial cells formed by Piezo1 proteins sense the physical force of shear stress to gate calcium entry which drives the vascular remodelling required for embryonic development. I showed this in mice but I also have evidence for its importance in cancer patients. In short, Piezo1 channels are pivotal in both the detection of physical force and its transduction into appropriate vascular architecture, which are enigmatic processes with significance across physiology and patho-physiology. Piezo1 channels are, however, only recently discovered large membrane protein complexes. There is only one homologue of Piezo1 and neither it nor Piezo1 shows significant resemblance to other membrane proteins. We know very little about Piezo1 and almost nothing about how it works in its c ritical physiological context of the endothelial cell. Here I propose research which will deliver important new mechanistic understanding of the Piezo1 protein and expand outwards from Piezo1 to provide step change in our appreciation of how vascular mechanical sensitivity works in physiology. This will be achieved by answering four key questions: 1. In what ways are the Piezo1 turret and its putative re-entrant loop important in endothelial biology? 2. How and why is Piezo1 localised to different cellular compartments in endothelial cells? 3. With which proteins does Piezo1 associate in endothelial cells and why? 4. What are the downstream pathways of Piezo1 in endothelial cells?

Where is this data from?

This data was originally published by The Wellcome Trust. If you see something about your organisation or the funding it has received on this page that doesn't look right you can submit a grantee amendment request. You can hover over codes from standard codelists to see the user-friendly name provided by 360Giving.

Grant Details

Amount Awarded 1821725
Applicant Surname Beech
Approval Committee Science Interview Panel
Award Date 2015-12-02T00:00:00+00:00
Financial Year 2015/16
Grant Programme: Title Investigator Award in Science
Internal ID 110044/Z/15/Z
Lead Applicant Prof David Beech
Partnership Value 1821725
Planned Dates: End Date 2022-06-30T00:00:00+00:00
Planned Dates: Start Date 2016-07-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Yorkshire and the Humber