A cross-disciplinary approach to understand the genetic risk of cardio(vascular) disorders –combining functional genomics to protein studies

Dr Samantha Pitt & Dr Silvia Paracchini

Deadline: 9^th May 2023

Funding: This is a funded 3-year PhD with Tenovus with fees and stipend (at UKRI rate) covered

Start date: September/October 2023

Summary: This project offers a unique training opportunity to bridge the gap between genomics and functional studies to answer fundamental questions underpinning cardiovascular health. We are looking for a candidate ready to be challenged and embrace a multidisciplinary approach.

Background: Cardiovascular diseases (CVDs) are a group of disorders of the heart and blood vessels. CVDs are the leading cause of death globally. This group of diseases include hypertension, stroke, coronary heart disease, heart failure, cardiomyopathies, rheumatic and congenital heart disease, and peripheral vascular disease. Changes in Ca²⁺ regulation can cause CVDs. Recently, our team discovered an important Ca²⁺ regulator and demonstrated its role both in heart function and in regulating blood pressure.

This new protein has never previously been reported in human diseases, however, we found individuals with genetic mutations in this gene were more likely to have vascular diseases, including hypertension, vascular dementia, diabetes, and heart disease and assume medication for hypertension and treatment of arrythmias. By taking advantage of large-scale publicly available data, we have been able to identify compelling associations. We found the strongest effect in the UK Biobank, which collates data for about half a million participants characterised with genetic, demographic, lifestyle data as well as their clinical history. The UK Biobank has allowed us to evaluate the role of our newly identified protein in human diseases. We found that

Project Outline: In this project we will take forward these very promising but preliminary findings. We will work with large datasets (e.g. the UK Biobank and SHARE) to evaluate the effects of these mutations at scale and analysing multiple layers of omics data . We will then characterise the most promising mutations with a range of molecular and functional assays, including CRISPR technology, single channel electrophysiology, physiological measurements of vascular function and live-cell imaging to assess Ca²⁺ store load and spontaneous Ca²⁺ oscillations in smooth muscle cells. The results will both advance our knowledge of the biological mechanisms underlying common diseases with the potential of identifying targets for early diagnosis and personalised treatment.

Previous relevant experiences in any of the areas including bioinformatics, computational biology, electrophysiology, and cell biology will be an advantage but are not a requirement. Full training in wet and dry techniques will be provided.

Expected value of results and impact: This project addresses a significant gap in the field of human genetics by dissecting the mechanisms linking genetic variation with human diseases with functional studies. The value of this project will be two-fold. First, we will be able to advance our understanding of the biology underlying common conditions. Second, the results will feed directly into the implementation of personalised medicine which will soon be a reality.

How to apply:

Full applications should be made via the University’s online portal.

Applications should include:

• CV or résumé. This should include your personal details with a history of your education and employment to date.
• A research proposal
• A sample of academic written work in English
• Academic transcripts and degree certificates.
• English language requirements certificate (if required)

Application enquiries can be made to Rachel Horn at [Email Address Removed].

Project enquiries can be made to Dr Samantha Pitt [Email Address Removed] or Dr Silvia Paracchini [Email Address Removed]