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H2020Individual fellowship2020–2022

PAELLA · Platelet Endothelial Aggregation Receptor 1

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2020-10-01 → 2022-09-30
EU contribution
€212,934
Participants
1
Scheme
MSCA-IF

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Results in brief

Platelet Endothelial Aggregation Receptor 1

Cardiovascular disease is the leading cause of death world-wide, affecting both men and women. Myocardial infarction and ischemic stroke are two severe consequences of cardiovascular disease caused by formation of an occlusive thrombus. Although advances in medicine have led to a continuing decrease in the number of cardiovascular disease-related deaths over recent decades, the improvement is stagnating, especially in younger individuals and in young women. New approaches are necessary to continue this downward trend. Blood coagulation and thrombus formation is a complex interplay between clotting factors, platelets and endothelial cells of the blood vessels that often involve interactions with leukocytes and other inflammatory cells. In a field in dire need of new treatment methods, we saw the potential importance of Platelet Endothelial Aggregation Receptor 1 (PEAR1), which is constitutively expressed on blood platelets, endothelial cells, and neurons. PEAR1 is an epidermal growth factor-like repeat receptor of uncertain function that has, repeatedly and independently, been associated with cardiovascular disease in genome wide association studies. The overarching aim of project PAELLA was to investigate the physiological role of PEAR1 and perform in-depth studies of PEAR1 signalling using synthetic agonists, exogenous agonists, and a new potential endogenous agonist.

Data: CORDIS, © European Union

Project objective

Cardiovascular disease is the leading cause of death world-wide, affecting both men and women. Myocardial infarction and ischemic stroke are two severe consequences of cardiovascular disease caused by formation of an occlusive thrombus. Blood coagulation and thrombus formation is a complex interplay between clotting factors, platelets and endothelial cells lining the blood vessels that often involve interactions with leukocytes and other inflammatory cells. I propose to study a novel receptor on platelets, PEAR1, and its role in haemostasis, inflammation and thrombosis. I will use unique, synthetic poly-sulfated sugars that I have characterised as novel agents to activate PEAR1 and take advantage of the 30 years of experience of my host, Professor Watson, in studying platelet activation, and the recent identification (unpublished) of the natural ligand in the body which activates PEAR1. I will use state-of-the-art methodology available in Birmingham including flow chamber studies, CRISPR-CAS knock-down, phosphoproteomics, super-resolution and light sheet microscopy, intravital microscopy and a PEAR1 deficient mouse model to test my hypotheses that PEAR1 plays a critical role in thrombus stabilisation at sites of injury and drives thrombo-inflammatory disease in the vasculature. Uncovering the role of the novel receptor PEAR1 may lead to new treatment strategies to combat thrombosis.

Original text from CORDIS.

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Data: CORDIS, © European Union