Non-coding NRP1 variants: suppressing soluble NRP1 to support vascular health?

Cardiovascular disease is a major cause of early death, including in the British Bangladeshi and Pakistani communities in East London. A key early event underlying cardiovascular disease is the dysfunction of the endothelial cells (ECs) which lines all blood vessels in the body. The project focuses on a protein called Neuropilin-1 (NRP1), which exists as a full-length form on the surface of ECs and shorter soluble forms (sNRP1) released into the blood. Our preliminary data show that inflammation increases sNRP1, that sNRP1 disrupts EC physiology, and that circulating sNRP1 is higher in patients whose coronary arteries narrow again after a stent has been inserted. Genetic studies have identified non-coding NRP1 variants associated with lower blood sNRP1, suggesting that these variants could be protective against cardiovascular disease.

The overarching aim is to determine whether NRP1 variants associated with lower sNRP1 reduce cardiovascular risk and to establish how they affect endothelial function. The student will combine genetic analysis of the Genes & Health bioresource, the world’s largest community-based genetic resource of British Bangladeshi and Pakistani populations, with clinical and proteomic datasets together with gene editing and in vitro functional assays in ECs. They will develop skills in statistical genetics, R-based data analysis, CRISPR/Cas9 genome editing, EC culture, qPCR, Western blotting, ELISA, fluorescent microscopy and endothelial functional assays.

Year 1: Obtain Genes & Health access and training; identify NRP1 variants associated with lower sNRP1; test associations with coronary artery disease, myocardial infarction, stroke and inflammatory markers; prioritise at least one lead variant for laboratory study.

Year 2: Generate and validate ECs carrying the selected variants and quantify the effects on full-length and soluble NRP1.

Year 3: Determine how the variant affects endothelial inflammation, leukocyte adhesion, permeability.

Year 4: Disseminate results at conferences, submit the PhD thesis, prepare a manuscript for publication.