Lithium is widely prescribed and the mainstay treatment for bipolar disorders. Unfortunately, lithium treatment often leads to adverse side effects (lithiopathies) like hypercalcaemia, nephrogenic diabetes insipidus and chronic kidney disease.
Despite the above lithiopathies, cessation of lithium therapy is not an option for most patients, because there is no good alternative and the bipolar disorder has a larger impact on the patient’s quality of life. However, rationally-based medication for lithiopathies exists. As the lithiopathies are largely irreversible, the medication should be administered with the start of lithium treatment. However, prophylactic administration of these medications to lithium-using patients is undesirable, because not all patients develop lithiopathies. Therefore, to target for lithiopathy-specific personalized prophylactic medication for lithium-using patients, the aim of this study is to identify the susceptibility genes for development of the lithiopathies.
To identify these susceptibility genes I propose to employ state-of-the-art haplotype association mapping (HAM) with mice at a world-recognized expertise centre for genetic research. As the used inbred mouse strains are fully genotyped, produce genetically identical offspring, and develop the lithiopathies consistently and on short term, HAM has clear benefits over genome-wide association studies in humans. At the return host, the role of identified susceptibility genes will be confirmed in cell and animal lithiopathy models and the corresponding orthologous genes in lithium-using patients will be tested for association with the lithiopathies. The project will not only provide the first steps towards personalized prophylactic medication for lithium users, but is also the perfect setup for a future scientific career of the applicant.
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