The Drosophila adult intestine as a model for radiation tolerance and resistance
Lead Research Organisation:
CARDIFF UNIVERSITY
Department Name: School of Biosciences
Abstract
Radiation therapy is an essential tool in the treatment of cancer. It is very cost effective, and responsible for 40% of cures, with chemotherapy contributing to 11% and surgery to 49% of cures. The reason why this treatment works is that radiation is toxic for all cells, but tumour cells are generally more sensitive to radiation. (Broadly speaking, the same principle applies to chemotherapy.) Treatment is applied with the aim of killing the tumour before causing too much damage in the healthy tissue of the patient. Therefore, radiotherapy can have serious side effects both shortly after treatment and in the longer term. Moreover, some tumours turn out to be very resistant to radiotherapy. The combination of this tumour resistance and the toxicity for the patient is an important limitation to the successful application of radiotherapy.
To overcome this limitation, we need to understand what are the causes of resistance in the tumours and of sensitivity in the healthy tissue. For instance, we know that tumours that switch on certain genes are protected from radiation; one could design a drug that prevents one of these genes from functioning and so improve the sensitivity of that type of tumours to radiotherapy. On the other hand, we need to understand how radiation causes malfunctioning in the healthy tissue. For instance, we know that specific cell types are particularly sensitive to radiation; identifying the factors that make them sensitive could help to design preventive or corrective treatments for the side effects of radiotherapy.
Research in this area is very active and has been identified as a priority for the UK by the National Cancer Research Institute. This type of research is conducted to some extent using cells in culture dishes. However, before any progress in medical practice takes place, research in whole animals (mostly mice and rats) is necessary, as it is not always the case that observations made with cultured cells are relevant to what happens in real tissues. With the aim of replacing the use of mice and rats, we want to establish the fruit fly as an alternative species where to study radiation sensitivity in whole animals.
Fruit flies are used for research in many areas of biology, as they are cheap and there are many experimental tools available to work with them. Moreover, the genes that provide resistance to radiotherapy in tumours have an equivalent in flies, and therefore knowledge obtained in flies about the functioning of these genes could have applicability in humans. We will focus on the fly intestine because many cancer patients have long-term intestinal side effects due to radiotherapy.
To test whether the fly intestine can be a useful research system to improve radiotherapy in substitution of rodents, we will seek to establish:
(1) whether the side effects of radiotherapy in humans are also mirrored in the fly intestine,
(2) whether we can identify genes and drugs that improve the tolerance of the healthy tissue, and
(3) whether we can create tumour-like cells inside the fly intestine that show increased radio resistance when they switch on the tumour radio resistance genes.
If we establish these observations successfully, this will indicate that the fly intestine can be used effectively in radiotherapy research in substitution of mice and rats, and we will advertise our findings to scientists working in this field, to encourage such replacement.
To overcome this limitation, we need to understand what are the causes of resistance in the tumours and of sensitivity in the healthy tissue. For instance, we know that tumours that switch on certain genes are protected from radiation; one could design a drug that prevents one of these genes from functioning and so improve the sensitivity of that type of tumours to radiotherapy. On the other hand, we need to understand how radiation causes malfunctioning in the healthy tissue. For instance, we know that specific cell types are particularly sensitive to radiation; identifying the factors that make them sensitive could help to design preventive or corrective treatments for the side effects of radiotherapy.
Research in this area is very active and has been identified as a priority for the UK by the National Cancer Research Institute. This type of research is conducted to some extent using cells in culture dishes. However, before any progress in medical practice takes place, research in whole animals (mostly mice and rats) is necessary, as it is not always the case that observations made with cultured cells are relevant to what happens in real tissues. With the aim of replacing the use of mice and rats, we want to establish the fruit fly as an alternative species where to study radiation sensitivity in whole animals.
Fruit flies are used for research in many areas of biology, as they are cheap and there are many experimental tools available to work with them. Moreover, the genes that provide resistance to radiotherapy in tumours have an equivalent in flies, and therefore knowledge obtained in flies about the functioning of these genes could have applicability in humans. We will focus on the fly intestine because many cancer patients have long-term intestinal side effects due to radiotherapy.
To test whether the fly intestine can be a useful research system to improve radiotherapy in substitution of rodents, we will seek to establish:
(1) whether the side effects of radiotherapy in humans are also mirrored in the fly intestine,
(2) whether we can identify genes and drugs that improve the tolerance of the healthy tissue, and
(3) whether we can create tumour-like cells inside the fly intestine that show increased radio resistance when they switch on the tumour radio resistance genes.
If we establish these observations successfully, this will indicate that the fly intestine can be used effectively in radiotherapy research in substitution of mice and rats, and we will advertise our findings to scientists working in this field, to encourage such replacement.
Technical Summary
Radiotherapy is a central component in cancer treatment due to its contribution to cures (40%) and its cost effectiveness. Its efficacy is hampered by the toxicity of radiation and the radio resistance of certain tumours. To overcome these limitations, we need to identify factors of tumour radio-resistance and organismal sensitivity, with the aim of developing treatments that combine radiotherapy with drugs that specifically radio sensitise tumour cells or protect the healthy tissue. This is an active area of research that has been become a priority in cancer research in the UK.
Before progress reaches the translational stage, in vivo evidence is essential in this field, and comes mostly from work on mice and rats. We aim at establishing Drosophila as an in vivo model for radiation research, to serve as Replacement for rodents. We will focus on the intestine, as this organ is highly similar in flies and mammals and it is of high medical relevance in cancer radiotherapy.
To establish the fly intestine as an in vivo model for radiation resistance and tolerance, we need to show that it mimics the basic phenomenology that we want to study. To do that, we will test whether:
(1) the fly displays intestinal malfunction (absorption, epithelial barrier) after irradiation,
(2) different cell types have differential sensitivity to radiation (as is the case in mammals) and the tissue engages in a regenerative response,
(3) we can observe cytoprotective effects after irradiation by either overexpressing in the fly gut factors known to enhance radiation tolerance or feeding flies with a radio-protective drug, and
(4) we can observe, in fly intestines that are genetically mosaic for factors known to confer radiation tolerance in tumours, differential radio-resistance between the mutant and wild type tissue. Establishing these observations would support our proposal that the fly intestine is a good in vivo model for radiation research that can replace the use of rodents.
Before progress reaches the translational stage, in vivo evidence is essential in this field, and comes mostly from work on mice and rats. We aim at establishing Drosophila as an in vivo model for radiation research, to serve as Replacement for rodents. We will focus on the intestine, as this organ is highly similar in flies and mammals and it is of high medical relevance in cancer radiotherapy.
To establish the fly intestine as an in vivo model for radiation resistance and tolerance, we need to show that it mimics the basic phenomenology that we want to study. To do that, we will test whether:
(1) the fly displays intestinal malfunction (absorption, epithelial barrier) after irradiation,
(2) different cell types have differential sensitivity to radiation (as is the case in mammals) and the tissue engages in a regenerative response,
(3) we can observe cytoprotective effects after irradiation by either overexpressing in the fly gut factors known to enhance radiation tolerance or feeding flies with a radio-protective drug, and
(4) we can observe, in fly intestines that are genetically mosaic for factors known to confer radiation tolerance in tumours, differential radio-resistance between the mutant and wild type tissue. Establishing these observations would support our proposal that the fly intestine is a good in vivo model for radiation research that can replace the use of rodents.
Planned Impact
Replacement
Our work aims at having the pre-existing community of radiation researchers as the agents of animal Replacement. If our pilot study is successful, we believe that we can present a compelling case for Replacement both in terms of scientific and economic reasons. With a strong case and our communication activity, we believe we can expect a Replacement in the order of ~3,000 animals per year.
Application
We aim at setting the grounds for translational studies oriented towards designing better radiotherapy treatments. This will include the development of functional assays to test candidate genes for tumour radio-resistance or tissue-sensitisation factors. Such assays have the potential to be applied at the genome-wide level. As they become established, we will be contacting potential industrial partners with the aim of further developing them into the drug-screening scenario. We will deliver this impact by working together with the Innovation and Engagement Office of (IEO) the School and the Research Innovation and Enterprise Services (RIES) of Cardiff University, both with a dilated track record of successfully establishing this kind of partnerships, will be involved in this process from the beginning.
Training
The PDRA will be trained in the use of the fly midgut, whose use in the Drosophila community is expanding exponentially. Beyond the scientific training, this project will give both the PDRA and JdN the opportunity to learn about translational research, from preparing the case for industrial partners together with the IEO and the RIES. A potential partnership will be explored in any case and this exercise will allow us develop important transferrable skills that are not usual for Drosophila researchers. Furthermore the establishment of Drosophila as a translational radiation studies will provide JdN a new avenue for establishing his career as independent researcher, and a competitive advantage to secure future funding. This impact will be delivered over the course of the funding period and its benefits will last beyond the span of the award.
Maintaining and enhancing the UK science profile
More generally, we believe that the completion and publication of this research will contribute to enhancing the profile of UK science, as we will be pioneering the use of Drosophila for radiation research at the cell and tissue level - which carries a strong potential for translational impact. Moreover this scope fits the EU's Horizon 2020 priority of "Understanding health, ageing and disease" and could be the seed for attracting research funding to the UK. Our publications and presentations will provide these impact benefits over the course of the grant, and facilitate new funding applications beyond the end of the award.
Engagement with the public
The completion of this project would provide a perfect case for explaining the use and utility of model organisms to the general public, which matches the general engagement activity that JdN has started as STEM ambassador. Our efforts to discuss our contributions with the general public will be under the umbrella of the IEO and the ECSCRI visitor's program, in the context of blogging and social media, and in open events in Cardiff University. Any published work will be flagged to our Press office for possible dissemination to the general press. These activities will progress throughout the period of the funding and continue beyond.
Our work aims at having the pre-existing community of radiation researchers as the agents of animal Replacement. If our pilot study is successful, we believe that we can present a compelling case for Replacement both in terms of scientific and economic reasons. With a strong case and our communication activity, we believe we can expect a Replacement in the order of ~3,000 animals per year.
Application
We aim at setting the grounds for translational studies oriented towards designing better radiotherapy treatments. This will include the development of functional assays to test candidate genes for tumour radio-resistance or tissue-sensitisation factors. Such assays have the potential to be applied at the genome-wide level. As they become established, we will be contacting potential industrial partners with the aim of further developing them into the drug-screening scenario. We will deliver this impact by working together with the Innovation and Engagement Office of (IEO) the School and the Research Innovation and Enterprise Services (RIES) of Cardiff University, both with a dilated track record of successfully establishing this kind of partnerships, will be involved in this process from the beginning.
Training
The PDRA will be trained in the use of the fly midgut, whose use in the Drosophila community is expanding exponentially. Beyond the scientific training, this project will give both the PDRA and JdN the opportunity to learn about translational research, from preparing the case for industrial partners together with the IEO and the RIES. A potential partnership will be explored in any case and this exercise will allow us develop important transferrable skills that are not usual for Drosophila researchers. Furthermore the establishment of Drosophila as a translational radiation studies will provide JdN a new avenue for establishing his career as independent researcher, and a competitive advantage to secure future funding. This impact will be delivered over the course of the funding period and its benefits will last beyond the span of the award.
Maintaining and enhancing the UK science profile
More generally, we believe that the completion and publication of this research will contribute to enhancing the profile of UK science, as we will be pioneering the use of Drosophila for radiation research at the cell and tissue level - which carries a strong potential for translational impact. Moreover this scope fits the EU's Horizon 2020 priority of "Understanding health, ageing and disease" and could be the seed for attracting research funding to the UK. Our publications and presentations will provide these impact benefits over the course of the grant, and facilitate new funding applications beyond the end of the award.
Engagement with the public
The completion of this project would provide a perfect case for explaining the use and utility of model organisms to the general public, which matches the general engagement activity that JdN has started as STEM ambassador. Our efforts to discuss our contributions with the general public will be under the umbrella of the IEO and the ECSCRI visitor's program, in the context of blogging and social media, and in open events in Cardiff University. Any published work will be flagged to our Press office for possible dissemination to the general press. These activities will progress throughout the period of the funding and continue beyond.
Organisations
People |
ORCID iD |
| Joaquin De Navascués (Principal Investigator) |