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

These research projects are in competition with 71 other studentship projects available across the GW4 BioMed MRC Doctoral Training Partnership. Up to 19 studentships will be awarded to the best applicants. Find out more information about the DTP including how to apply.

Radiotherapy (RT) is an essential component of cancer treatment. Its efficacy is greatly limited by the chronic side effects of radiation injury, which can be severe and are difficult to predict.

The project aims at identifying biomarkers of chronic radiation toxicity using Drosophila melanogaster, to eventually personalise RT doses in patients.

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 availability of biomarkers to stratify patients according to radiation sensitivity would allow 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. You will record lifespan and intestinal function traits after sub-lethal irradiation in a collection of ~40 strains from the Drosophila Genetic Reference Panel (a collection of highly inbred, fully genotyped lines), selected by their identification as resistant or sensitive to lethal radiation. 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 most of the training in fly husbandry, bioinformatics and genetic analysis.
  2. Candidates from phase 1, the literature, and unpublished work from JdN’s lab will be assessed for priority, based on their conservation in humans, availability of in vivo tools, molecular function, and gene expression.
  3. 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 late radiation toxicity using additional methods (microscopy, histology, immunofluorescence).

Supervisors

Dr Joaquín de Nevascués Melero

Dr Joaquín de Navascués Melero

Research Fellow

Email:
denavascuesj@cardiff.ac.uk
Telephone:
+44 (0)29 2068 8515

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