Dr. Alexander Crawford (AC) leads the Chemical Biology group at LCSB. The group uses disease modelling and chemical biology approaches in zebrafish to understand the molecular mechanisms – and therefore potential therapeutic entry points – involved in central nervous system disorders such as epilepsy and Parkinson’s Disease. One focus is the epileptic brain: how do seizures arise from mutations occurring in rare genetic epilepsies? The group uses a combination of behavioural, electrophysiological and pharmacological approaches to characterise epileptic seizures in zebrafish models genetically modified to have a complete or partial loss of function of disease-relevant genes identified in human epilepsy patients. As most of these rare genetic epilepsies are pharmaco-resistant (i.e., patients do not respond to existing anti-epileptic drugs), the group seeks to understand the molecular and neuro-cellular mechanisms involved in the emergence of seizures from their underlying genetic defects, with the goal of identifying novel therapeutic entry points that might enable the development of new, effective anti-epileptic drugs capable of treating these disorders. Towards this end, the group uses zebrafish models of human epilepsies to perform chemical modifier screens with libraries of drug-like small molecules. Active small molecules identified in such screens will not only enable the development of novel drug leads for these rare genetic epilepsies; in addition, the identification of their modes of action and their biomolecular targets will elucidate the molecular mechanisms that govern seizure control – i.e., the critical transition between normal brain activity and abnormal, excessive and/or synchronous neuronal activity in the epileptic brain.
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