David Baker’s research group uses biochemical and genetic approaches to study the cyclic nucleotide signal transduction pathways of malaria parasites. The cyclic nucleotides cAMP and cGMP perform a whole spectrum of cellular functions in diverse organisms. Earlier work from other laboratories suggested that both of these second messenger molecules may play roles in malaria parasite differentiation. David's studies have focused on the cyclase enzymes that synthesise cyclic nucleotides, the phosphodiesterases that degrade them, but also on the protein kinase that is activated by cGMP (PKG). David's group have found that in Plasmodium falciparum cGMP and PKG play an essential role in triggering the activation of mature sexual parasite forms (gametocytes) which are required to transmit disease to the mosquito vector. As part of a collaboration they also showed that this pathway is important for the development and motility of the ookinete form of P. berghei within the mosquito. It is now becoming clear that cGMP signalling and the PKG enzyme are vital for multiple parasite stages, because using specific PKG inhibitors in conjunction with inhibitor-insensitive transgenic parasites David's team have demonstrated that asexual blood stage schizogony cannot progress if this kinase is blocked. With others they have shown that PKG functions upstream of a protease cascade and a calcium-dependent protein kinase (CDPK5) also required for asexual blood stage schizont rupture and merozoite egress. More recently, through another collaboration, they showed that PKG activity stimulates calcium release required for merozoite egress and that this is likely mediated through regulation of phosphoinositide metablism. Since drug resistance is a huge problem, David's group are investigating whether cyclic nucleotide signalling pathways could be targeted in the development of novel antimalarial drugs. 

David received a Wellcome Trust Senior Investigator Award in 2015. This is a joint award with Professor Mike Blackman at the Francis Crick Institute that will focus on the cGMP signalling pathway in malaria parasites.