Genome-wide analysis of mechanosensitive channels in cardiometabolic diseases.
Approved Research ID: 85253
Approval date: August 9th 2022
The primary objective of this proposal is to identify the genetic associations of mechanosensitive channels in cardiovascular and metabolic diseases. We will study the diseases, including heart failure, hypertension, and diabetes. This aim will be achieved by conducting genome-wide association studies focused on mechanosensitive channels and interrogate heart and liver imaging data through UK Biobank data. This proposal is linked to our previous analyses where we performed the gene-level analysis of PIEZO1 and ORAI1 to cardiometabolic disease. However, we will extend this analysis genome-wide and screen the heart and liver imaging data. The overall aim is to improve cardiovascular disease prevention, diagnosis, and treatment by identifying genetic variants and risk factors. The insights from this proposal will guide us to a better understanding of cardiovascular and metabolic medicine and, ultimately, the development of new therapeutic targets. This work will require access to the UK Biobank whole-genome, whole-exome, metabolomics and heart MRI imaging. We have extensive experience in mechanosensitive channels such as PIEZO1 and ORAI1. These channels are expressed in a wide range of cell types essential in human diseases. Inhibition of these targets appears to be beneficial and potential therapeutic targets. We aim to use the same approach to study other mechanosensitive channels implicated in cardiovascular disease. The data from UK Biobank will inform us about the novel mechanosensitive channels in cardiovascular disease and prepare us to bid for drug discovery programme grants. Over the 36 months, we will screen UK Biobank for all the mutations present within mechanosensitive channels and association with heart failure, hypertension and diabetes. Once we find some genetic variants, we will validate these mutations using our established cell culture systems to test the function. Our ultimate aim is that this proposal will lead to discovering other important mechanosensitive channels linked to cardiovascular diseases and new therapeutics targets.