KESS2 PhD in Biosciences: A Drosophila in vivo platform for the identification of radiation sensi...
Radiotherapy is an essential component of cancer treatment, indicated to ~50% of all cancer patients, responsible for 40% of cures, and very cost effective (5% of the cancer care costs).
However, its efficacy is limited by the toxicity of ionising radiation to the normal tissue, whose effects can be both acute (hours to weeks after treatment) and chronic (months to years). Late effects can be very serious and have a great impact in the quality of life of cancer survivors, years after treatment. With an increasing population of cancer survivors (2 million in the UK, of which probably ~100.000 are in Wales), chronic radiation injury is a mounting health care concern.
Currently, radiotherapy doses are generally defined so that less than 5% of patients will suffer serious late toxicity. Thus, the ability to stratify patients according to biomarkers of radiation sensitivity would be highly desirable, as it would allow prescribing personalised radiation doses. Likewise, insights into the nature of late toxicity could lead to co-treatments to ameliorate these side effects.
The project aims at identifying potential biomarkers for predisposition to chronic radiation injury in cancer patients receiving radiotherapy. To model late radiation injury in a genetic organism, we will use the fruit fly, Drosophila melanogaster, with assays for this purpose developed in JdN's lab with support from the NC3Rs. The experimental plan will include quantitative genetics to identify loci potentially involved in radiation tolerance, functional genetics using the Drosophila genetic toolkit to validate candidate genes identified by the quantitative genetics approach as well as those obtained from the literature and previous work in JdN's lab.
The work plan is divided in three phases, which will be performed sequentially or in parallel as the project develops:
First, you will record lifespan and intestinal function traits after sub-lethal irradiation in a targeted sub-collection of the Drosophila Genetic Reference Panel (a collection of highly inbred lines that has been fully genotyped). With the phenotypic data generated and the genotype of these lines available, a quantitative genetic analysis will be performed to identify regions of the genome associated with either resistance or sensitivity to late radiation resistance. This phase will coincide with the training in fly genetics, bioinformatics and quantitative genetic analysis.
Candidates from phase 1 will be assessed for priority based on their conservation in humans, availability of mutants, molecular function, gene expression, etc. Our partner Tenovus will be highly involved in this phase. This phase will be developed in parallel with the first as much as possible.
The top 10-15 candidates will be functionally validated for an effect on late radiation toxicity, using available mutants as well as UAS-controlled gene-specific RNAi transgenes (expressed with a ubiquitous driver such as tubulin-Gal4 or, whenever the gene is expressed in a tissue-specific fashion, the corresponding tissue-specific Gal4 driver). One or two validated genes with a suggestive biological mechanism will be further studied, to gain insight into the cellular and molecular basis of their role in radiation toxicity using additional methods (microscopy, immunohistochemistry) to obtain additional insight into the origins of late radiation injury.
Please take note that this is a distinct funding opportunity from a related project advertised under the GW4 BioMed Doctoral Training Partnership (A Drosophila in vivo platform for the study of chronic radiation injury); each opportunity corresponds to related, but non-overlapping projects, and have different eligibility requirements.
This job comes from a partnership with Science Magazine and