In this thesis we describe a set of studies, performed using rodent models of malaria, aimed to identify methods to improve vaccines consisting of live attenuated sporozoites, in particular... Show moreIn this thesis we describe a set of studies, performed using rodent models of malaria, aimed to identify methods to improve vaccines consisting of live attenuated sporozoites, in particular genetically attenuated parasites (GAP) vaccines. Studies in rodents and humans have shown that immunization with live-attenuated sporozoites can generate protective immunity, however induction of sterile protection in humans has required immunization with multiple vaccine doses and each dose consisting of relatively high numbers of sporozoites. Increasing the immunogenicity of whole sporozoite (wsp) vaccines can both reduce the number of sporozoites per dose and the number of vaccine doses. In the studies described in this thesis we attempted to increase GAP immunogenicity by: (i) adding adjuvants during GAP immunization; (ii) introducing genes encoding putative immunomodulatory proteins in the GAP genome to create ‘self-adjuvanting’ parasites; (iii) generating GAPs that arrest late into liver-stage development (LA-GAP) to increase antigen load and diversity during immunization; and (iv) exploring possibilities to genetically modify parasite to express vaccine antigens from different life cycle stages, in order to test the ability of parasites to induce immune responses against multiple life cycle stages and to inform the creation of a ‘multi-stage’ GAP vaccine. Show less
The aim of the studies described in this thesis was to investigate how abnormal CaV2.1 channel function can cause disease, in particular motor coordination dysfunction. The chapters illustrate how... Show moreThe aim of the studies described in this thesis was to investigate how abnormal CaV2.1 channel function can cause disease, in particular motor coordination dysfunction. The chapters illustrate how various neuronal cell types in the periphery (peripheral nervous system) and the central nervous system are affected by mutations in subunits of CaV2.1 channels. Using existing and newly generated mouse models, the consequences of such mutations were investigated at the molecular, cellular, and systems level so as to unravel pathways involved in motor coordination. Show less
