The Wellcome Trust Strategic Award DEFINE Grant
DEFINE offers an integrated basic and clinical neuroscience programme to explore mental disorders.
This project is developing an integrated basic and clinical neuroscience programme to study the effects of high-penetrance mutations conferring risk for mental disorder across current diagnostic boundaries.
Our objective is to identify valid animal and cellular phenotypes for future target validation and drug screening and to identify biomarkers of fundamental disease processes for patient stratification.
This programme comprises three linked themes each with its own objective.
We are generating and characterising rodent models with mutations in specific synaptic proteins that confer high risk for psychiatric disorder, as implicated by our genetics programmes. These studies utilize closely integrated behavioural, electrophysiological, optogenetic and imaging studies to understand the synaptic and circuit-level impacts of these mutations which underlie risk for a range of mental disorders.
This work will expand over time to include the investigation of pharmacological challenges and provide a basis for future investigation of gene-environment interactions.
We are, in parallel, recruiting patients with deleterious mutations in the same genetic targets as our animal studies. Participants have been selected on the basis of underlying genetic mutations rather than on the basis of categorical diagnosis. Patients have been phenotyped using a tailored suite of behavioural, electrophysiological and brain imaging measures linked to our pre-clinical studies.
These results will be compared to findings in genetically unselected patients to determine the generalisability of our findings and the potential for patient stratification.
We have developed cellular models of the effects of the same mutations derived from our animal models and from patients carrying identified genetic lesions.
These cellular models provide valuable additional tools that complement systems-based studies in animals and patients. They also:
- allow us to correlate behavioural and physiological measures with cellular pathology
- create an additional interface between our animal and human studies
- allow temporal analysis of disease initiation and progression to be studied in neuronal subtypes relevant to disease
- ultimately create a major platform for future early phase drug discovery.
For more information regarding the Wellcome Trust Strategic Award Define Grant, please contact: