A Drosophila in vivo platform for the study of chronic radiation injury

Radiotherapy is an essential component of cancer treatment, indicated to ~50% of all patients, responsible for 40% of cures, and taking only 5% of the cancer care costs. Its efficacy is limited by ionising radiation injury to the normal tissue, which can become chronic. These late effects may be very serious and can affect the quality of life of cancer survivors, years after treatment. With an increasing population of cancer survivors (2M in the UK), chronic radiation injury is a mounting health care concern. Radiotherapy doses are generally defined so that less than 5% of patients will suffer serious late toxicity. The better understanding of the genetics underlying radiation sensitivity in patients would allow their stratification, prescribing stronger radiation doses to resistant patients and milder ones to those susceptible of suffering from late toxicity. Likewise, insights into the nature of late toxicity could lead to co-treatments to ameliorate these side effects. The project aims at identifying genes involved in the predisposition to chronic radiation injury, using Drosophila melanogaster and assays that model late radiation injury in the fly intestine, developed in JdN’s lab. Identified genes could point at human homologs as potential biomarkers of susceptibility, and provide useful mechanistic understanding for the design of better treatments.

The experimental plan is divided in three phases, which will be performed sequentially or in parallel as the project develops:
1. The student will collect RNAseq at different times post irradiation, from both intestines and whole flies of the reference background genotype, to have an insight into the transcriptional changes associated with late radiation injury.

2. The student will record lifespan and intestinal function traits after sub-lethal irradiation in a collection of mutants for several candidate genes (taken from the literature, preliminary work from JdN’s lab, and genes selected by RNAseq). As lifespan is a strongly polygenic trait this will require back-crossing the mutations into a reference background genotype. These two phases will coincide with most of the training in fly husbandry, bioinformatics and genetic analysis.

3. The top 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 late radiation toxicity using additional methods (microscopy, histology, immunofluorescence).


For further details of this project, please see our website: http://www.cardiff.ac.uk/study/postgraduate/research/programmes/project/a-drosophila-in-vivo-platform-for-the-study-of-chronic-radiation-injury