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Investigating the effects of PCSK9 on inflammation in clinically relevant human models of ARDS

School of Medicine, Dentistry and Biomedical Sciences | PHD

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Funding
Funded
Reference Number
SMED-2231-1224
Application Deadline
None specified
Start Date
None specified

Overview

This project will investigate the effects of a PCSK9 inhibitors, drugs developed for cholesterol reduction, on inflammatory mediator expression in cell types implicated in the development of Acute Respiratory Distress Syndrome, using a range of experimental techniques including cell culture, single cell RNA sequencing, ELISA and Luminex.

Acute Respiratory Distress Syndrome (ARDS) is a common condition in critically ill patients requiring mechanical ventilation, and is often found in association with sepsis and other systemic illnesses. ARDS is associated with a high mortality, and there are no effective pharmacological interventions.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are drugs which lower Low Density Lipoprotein (LDL)-cholesterol and reduce cardiovascular events in at-risk patients. The mechanism of cholesterol reduction is increased cellular LDL receptor recycling resulting in increased clearance of LDL-cholesterol from the circulation.

PCSK-9 inhibitors have been shown to increase clearance of lipopolysaccharide (LPS), a key pathogen-associated molecular pattern (PAMP). LPS is a component of the cell wall in gram-negative bacteria which acts through Toll-like receptor 4 and other mechanisms to induce a potent inflammatory response and appears to be a major driver of sepsis and ARDS.

In this project, we will investigate the effects of PCSK-9 inibitors on the expression of inflammatory mediators in cells which are involved in the inflammatory pathways in ARDS: specifically alveolar macrophages and pulmonary microvascular endothelial cells (HPMVECs), co-cultured aveolar macrophages and HPMPVECs, and finally in a human precision cut lung slice (hPCLS) model.

Funding Information

Project Summary
Supervisor

Dr Jon Silversides

More Information

askmhls@qub.ac.uk

Research Profile


Mode of Study

Full-time: 3 years


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