FlyMet.org - a tissue-based metabolomic online resource for the Drosophila and systems biology communities

Lead Research Organisation: University of Glasgow
Department Name: College of Medical, Veterinary &Life Sci

Abstract

All living organisms have a metabolism - a set of hundreds or thousands of chemical reactions that allows them to survive. Recent technologies have allowed us to take a chemical snapshot of hundreds of such chemicals - a 'metabolome' - that provides a sensitive indicator of what is going on inside the organism, its health and nutritional status. In our bodies, as in all multicellular organisms, the metabolomes of different tissues are likely to differ significantly, reflecting the different specialized jobs they perform.
Obviously, this is hard to study in humans. However, the tiny fruit fly, Drosophila, has proved itself to be an ideal 'model' for many human processes. For example, much of our understanding of how humans develop, or of how our body clocks work, is based on research first performed in Drosophila. So this project is to generate metabolomes for the major tissues of Drosophila, and to place them online in the public domain, together with computer models of each tissue's metabolic 'map'. Such a dataset will be invaluable for the rapidly growing population of scientists studying metabolism in Drosophila - for example to model the natural ageing process or obesity and diabetes - and may provide modelling techniques and tools to let us understand more of human biology. Similarly, 70% of human genetic diseases are mutations in metabolic enzymes. They can either be directly harmful, or damage organs like the kidney by uncontrolled accumulation of metabolites. 80% of human genes have Drosophila homologues, and so it is possible to model many inborn errors of metabolism in the fruit fly, assess the impact of mutations by metabolomic approaches, and use such mutants in drug screens to alleviate these life-threatening conditions.
The benefits of the project are not likely to be specific to biomedicine; for example, a million lives are still lost annually to insect-borne diseases such as malaria and dengue; and insects are also key vectors of animal disease, such as blue tongue virus. Drosophila, with its potent genetic tools, is an ideal model for insect pests. Understanding insect metabolism may help us understand how insects render insecticides harmless, or even identify new targets for novel, greener, insecticides.

Technical Summary

This project is to open up a new area, by generating an authoritative metabolomic tissue 'atlas' of Drosophila, and linking it to FlyAtlas.org, our existing transcriptomic atlas resource, and to our recently developed computational model for insect metabolism. We will microdissect multiple tissues from adult and larval Drosophila, and subject samples to three different chromatography-MS protocols in order to maximize the molecular coverage of our metabolomes. The results will be placed in the public domain through accepted repositories, such as EMBL-EBI's Metabolights; and through our own FlyMet.org resource, which (like flyatlas) will be designed to be as accessible as possible to a non-specialist audience. In parallel, we will develop our metabolic model of Drosophila, using FlyAtlas data to identify regions of the global metabolic map that are particular to individual tissues; and use FlyMet data to directly validate the predictions. We will also use reverse genetics to try to fill any gaps in our metabolic model. The end result will be a public domain tissue-specific metabolomic resource that will be unique and of value to a rapidly growing cohort of scientists interested in metabolic processes in Drosophila and beyond.
This work will have impact in three areas: (i) in applied biology, where Drosophila, with its potent genetic tools, is an ideal model for insect pests. (ii) in systems biology Drosophila, with its metazoan body plan and powerful genetics, provides an ideal compromise in which to work up the concept of tissues in systems biology. (iii) In biomedicine, 70% of human genetic diseases are mutations in metabolic enzymes. Metabolomic resources will provide valuable baselines against which to delineate Drosophila models of disease.

Planned Impact

This work will benefit the UK/international academic community, the wider public, inform policy makers and in the longer-term, fulfill economic impact.

Academic community: in addition to that described in 'Academic Beneficiaries', our work will be disseminated via meetings, publications and collaborations (Pathways to Impact). In 2015, Julian Dow (JATD)/Shireen Davies (SD) fulfilled >75 requests for transgenic flies and antibodies; and received many requests for information/discussion, so we are of real benefit to the Drosophila/insect community. The investigators have collaborations with key UK and international groups in their fields (e.g. JATD with the 'omics community; SD/JATD with neuroendocrinology researchers, e.g., nEUROSTRESSPEP consortium; KB with the metabolomics community), and so are well positioned to develop avenues of investigation of mutual interest during the course of the grant. We will also develop highly trained researchers for the academic or industrial market. This extends beyond the researchers directly employed on the project, to other members of the lab, including PhD, Masters and undergraduate project students.

Economic impact: This work will aid in the identification of suitable simple models, and screening for novel treatments. It will also provide novel datasets for exploitation towards application in crop protection and capacity building for insect molecular science research for Food Security and Clinical Science. The investigators have current collaborations and partnerships with industry that can also be targeted via knowledge exchange and promotion of activities (e.g. workshop, see Pathways to Impact); and can be approached for joint exploitation of relevant findings, managed by University of Glasgow's Research Strategy and Innovations Office.

Public engagement, societal and policy impact: We have had good engagement with the public via the media and also BBSRC Business, International Innovations, Public Science Review, University of Glasgow communications office. Dow/Davies's research work may form a REF2020 impact case study and is also exhibited at the Glasgow Science Centre (Images on the Clyde). Our work also featured in the recent BBSRC Excellence with Impact 2016 competition, in which UoG was ranked top institution. We also undertake activities at the Glasgow Science Festival, so reaching a wide public audience.
Also, interactions with identified stakeholders including policy makers (e.g. towards Guidelines on screening for Inborn Errors of Metabolism) and dissemination activities to end users, will help achieve long-term societal and policy impact.

Project Management: All the investigators play active roles in project management, essential to achieve measurable output/progress for all aspects of funded research. We utilise BaseCamp, a platform for project management that allows project-specific data display, discussion and planning, to which group members have secure access. We also have regular project meetings with team members, with additional weekly Drosophila group meetings (SD/JATD) as a forum for group discussion and presentation.

All the investigators have excellent, relevant track records in output; collaborations and exploitation; and communication and engagement - so can achieve the maximum outputs and impact from funded projects.

Publications

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Dow JA (2018) New views on the Malpighian tubule from post-genomic technologies. in Current opinion in insect science

 
Description NIH Centre grant
Amount $400,000 (USD)
Funding ID DK100227 
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 03/2013 
End 03/2018
 
Description Collaboration with BASF 
Organisation BASF
Country Germany 
Sector Private 
PI Contribution Based on our leading position in insect biology and functional genomics, we have had longstanding collaborations with BASF in RTP, North Carolina. We have performed extensive contract research over 5 years, and continued to discuss possibilities for the development of new targets. We have also tested novel compounds from BASF against in-house assays.
Collaborator Contribution BASF have funded extensive periods of contract research with our group, and paid us for consultancy when testing novel compounds. They have also hosted a FLIP award with our group, led by Professor SHireen Davies, giving us access to leaders in several of the key chemistry, mode-of-action and regulatory groups in North Carolina. This has informed our plans to develop a spin-out from our research.
Impact Large gene expression datasets and fly lines developed. Details are confidential.
 
Description Collaboration with Bayer 
Organisation Bayer
Department Bayer CropScience Ltd
Country United Kingdom 
Sector Private 
PI Contribution Our identification of processes involved in the generation of extreme pH in insect guts has the potential to lead to new, greener, more selective insecticides at a time when there is field resistance to all commercial insecticides. This work has led to approaches from industry.
Collaborator Contribution Bayer approached us to discuss our plans to commercialize this research. They duly completed 2-way NDAs with the University of Glasgow, and held a conference call with us in February 2018. They are excited by the possibilities, and plan to discuss further once the merger with BASF is complete.
Impact N/A
Start Year 2017