Leishmaniasis is a medically important disease exclusively transmitted by phlebotomine sand flies. The ecology of the sand fly-Leishmania relationship is complex, the possibility that larval stressors carry over to impact on the adult sand fly-Leishmania relationship have not been considered. Knowledge of the impact of larval stress on adult transmission of disease would help us understand the basis of susceptibility/refractoriness to Leishmania and affect our capacity to contain disease outbreaks. The project will involve working on a Brazilian strain of Lutzomyia longipalpis that is the vector for Leishmania infantum in S. America. The project is in collaboration with Dr Mauricio Sant'Anna at a Brazilian University (UFMG, Belo Horizonte) and will involve a collaborative visit to Brazil.
Supervisor: Dr Rod Dillon
Based on preliminary data it is proposed to undertake a Synthetic Genetic Analysis (SGA) screen in fission yeast designed to identify and analyse the functional genetic architecture supporting TopBP1 activity. TopBP1 is highly conserved in the eukaryota and functions in the initiation of eukaryotic DNA replication as well as having a central role in the cellular response to the presence of DNA damage. Compromise of both the initiation of DNA replication and checkpoint function have been widely implicated in the initiation of neoplastic growth. A preliminary screen has identified a number of functional groups of genes that when mutated are synthetically lethal in combination with a hypomorhic allele (rad4-116) of the gene encoding the S. pombe TopBP1 homologue. It is proposed to repeat the preliminary screening process to generate a statistically robust dataset and in parallel to analyse some of the potential genetic interactions uncovered in that preliminary screen. These functions relate to chromatin structure and maintenance, with a particular focus on the replication and structure of heterochromatin at centromeres and telomeres and the role of recombinational repair under conditions of replication stress. Methodology to be employed beyond the initial synthetic lethality screening will include quantative fitness analysis, gene expression analysis by quantitative PCR, two dimensional gel analysis of DNA replication intermediates, time resolved study of DNA replication using fluorescent labelling technologies and microscopy (DNA combing), time resolved live cell imaging microscopy.
Supervisor: Dr Clive Price
The project will use molecular biology techniques to study mosquitoes, with the aim of contributing to the development of novel biological and genetic strategies for controlling mosquito-borne pathogens such as malaria parasites and arboviruses. Based at Lancaster University, it will also involve a period of at least one year based at Oxitec Ltd., a leading biotechnology spin-off company based in Oxfordshire.
Supervisor: Professor Steven Sinkins
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