Aims. 1. Identify, 2. Characterize proteins involved in human physiology and several pathologies, 3. Provide genotypic-pharmacologic-phenotypic correlations, and 4. Orientate Drug Discovery efforts to pharmacologically validated wild-type and variant targets.
Scientific Rationale. GPCRs represent the largest protein family and transduce extracellular messages to intracellular signalling. They mediate the therapeutic effects of more than one third of the marketed drugs. The first DNA variation leading to a change in the amino acid sequence was published in 1993. For example, a missense variation was identified by the sequencing of genomic DNA from normal subjects and those with asthma. This genetic modification leads to dramatic variation in the response to endogenous ligand and translate to the disease. This initial study and other support the approach that signalling phenotypes of patients displayed clinically significant phenotypic differences or response to therapy when grouped by genotype. UK Biobank provides a unique opportunity for combinations of variants and to discover and work on the best predictors of certain responses to endogenous ligands and to drugs.
Project Duration. A 36-month program. We will assess the effects of human endogenous molecules on 200 membrane targets. 750 drugs, that are or were tested in Clinical Trials, will be profiled on those 200 receptors. In parallel, target variants identified from UK BioBank will be synthesized and their functional response to their endogenous ligands will be evaluated. Their response profiles will be compared to the wild type form. Positive correlation will be assessed between the variants -pharmacological response – phenotype described within UK BioBank.
Public Health Impact. An important priority for public health practice today in genomics is to serve as an honest broker of evidence-based processes to inform providers, the public and policy makers whether the deployment of a particular technology for a particular intended use can have a net positive health impact on the population. Genomic science has given greater emphasis to the importance of molecular and cellular mechanisms in health and disease. Pharmacological knowledge should be integrated with the genomics to improve health both at the individual and population levels. These approaches will be at the heart of the growing discourse around personalized medicine, the idea that medicines and other health technologies including the prediction of individual risk may be customized to each person’s specific genetic, physiological, or psychological characteristics.
