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Approved Research

A Genome-Wide Study of clinically relevant G-Protein Coupled Receptor Variants

Principal Investigator: Dr Jens Kleinjung
Approved Research ID: 72673
Approval date: May 13th 2022

Lay summary

The project aims at the development of novel medicines for diseases that are related to structures, so-called receptors, which are located on the outside of cells in the human body and that can bind certain substances and thereby convey signals to the inside of the cell. In this project we focus on a particular kind of receptors, the "G-protein coupled receptors" (GPCRs). GPCR receptors are important for conveying signals originating from nerves, hormones, and the immune system, which are all important for keeping the body in a balanced healthy state. The central role of receptors in signalling makes them important drug targets. However, only a minority of GPCR receptors are currently used in medical treatment, because our knowledge about them is incomplete.

In this project, which we estimate to take about three years, we would like to use differences in the genetic information among people, and to link their medical records to identify receptors that could be involved in diseases.

About 60 new changes per generation are added to a person's genetic material (DNA), and over time many of those changes --- called mutations --- have also affected GPCR receptors, as these receptors are encoded by the human DNA sequence.

The GPCR mutations that we will see in healthy people in this project will enable us to make modified GPCRs with normal function. The GPCR mutations that turn out to be related to diseases will be engineered to study their modified function.

Most diseases can be traced back to a genetic origin, often involving multiple mutations. By analysing the genetic information of many people, we can determine which mutations are associated with groups of people who are affected by a disease compared with groups of healthy people. GPCR receptors carrying disease-related mutations can be made and tested for their biological function or interaction with potential drug molecules. We intend to study diseases related to inflammation (for instance, gut inflammation) and neurodegeneration, which is the irreversible loss of nerve cells, leading to dementia. Alzheimer's disease is the most common cause of dementia, and therefore it is important to find treatments to cure it. The relatively large number of people present in the UK Biobank (or their relatives) who are affected by Alzheimer's disease also means that we can fruitfully use the data collected in the UK Biobank to relate GPCR receptors to neurodegeneration.