A new vessel in the fleet: exploring how enteric tracheal plasticity drives metabolic adaptation in Drosophila

Our gastrointestinal tract has important functions that go beyond digesting the food we eat. It can also communicate with organs such as the brain to change our appetite or how our body stores excess nutrients. This communication is, however, incompletely understood; what kind of information is the digestive tract able to sense, and how can it relay it to other organs? If we were able to understand better how this happens, it may be possible to use drugs to "trick" the digestive system into making us eat less or get less fat. Investigating this in humans or model systems such as mice is complex, however; they have many cells of many different kinds that are not always easy to probe to identify the ones that matter, and to understand how they signal or receive information. Instead, we tackle this question in the fruit fly Drosophila melanogaster: a simpler model system that shares 60% of our genes. Drosophila has a functionally sophisticated yet genetically tractable digestive tract. We recently found that the fly vessels that, like our vascular system, deliver oxygen to the gut cells play an important and previously unrecognized role in this communication. Indeed, these vessels -the so-called trachea- change their branching in response to specific nutrients. This somehow allows flies to cope with malnutrition and also affects how much fat they store in their bodies. This proposal seeks to understand what the branching of trachea does to other gut cells and how these gut cells, in turn, are able to affect metabolism and the fly's response to malnutrition. Our experimental design will first take an unbiased approach to characterize how differences in tracheal branching affect the expression of genes in the gut, and will then focus on a subset of these changes to understand how they affect the metabolism of the gut cells and their signalling to other organs. We anticipate that our research will both shed light on fundamental mechanisms of inter-organ communication and also identify potential new drug targets for the treament of nutrition-related diseases and conditions.

Incompletely understood signals and metabolic adaptations emanating from the gastrointestinal tract contribute to both increasingly prevalent metabolic disorders as well as to the sustained metabolic improvements resulting from bariatric surgery. Our previous work has made use of the analogous, yet genetically tractable, digestive system of the fruit fly Drosophila melanogaster to explore the mechanisms by which this organ communicates with other internal organs to maintain homeostasis. Our recent work identified an important and previously unrecognized role for enteric trachea (the fly vessels that, like our vascular system, deliver oxygen to the gut cells) in driving metabolic adaptations to malnutrition that enhance survival. This proposal will now seek to identify and characterize the intestinal changes responsible for these adaptations. Temporally and spatially restricted genetic manipulations of enteric tracheal branching will be combined with tissue-specific transcriptional profiling of the Drosophila midgut to provide a comprehensive characterisation of how tracheal plasticity impacts intestinal gene expression. Subsequent work will focus on a subset of these changes to establish how these intestinal adaptations modulate organismal physiology. We anticipate that our research will both shed light on fundamental mechanisms of inter-organ communication and also identify potential new drug targets for the treament of nutrition-related diseases and conditions.

The research will contribute to the nation's culture, and has the potential to generate wealth and improve health:

1. Culture. We will continue to reach out to public audiences through engaging presentations and innovative workshop formats in order to increase their awareness of the utility of fruit flies as model systems for biomedical research. Specific activities will include:
a) My participation in workshops such as the recent "Fabrics of life" workshop where I and other scientists disseminated the latest in scientific research to the arts community. During the 2014 "Big Data"-themed event, I engaged with architecture and textile design students and professionals, and students had the chance to brainstorm ways of translating scientific principles into design models.
b) My team's and/or my own contribution to hands-on activities for the general public, implemented within the framework of the annual Imperial College festival, the National Science & Engineering week, local school visits and the bi-annual school workshops in the Imperial College Teaching Labs. These will allow the general public to meet scientists and learn about their daily work. Modules will be based on the research outlined in this proposal, and will be aimed at highlighting the similarities between the digestive and vascular/respiratory systems of flies and humans, as well as their physiological significance. We have previously run - and evaluated quantitatively - similar activities, and we know that they can help bridge the gap between scientists and the general public.

2. Health. This project has the potential to identify genes and pathways which could become drug targets for the treatment of malnutrition or metabolic disorders involving the digestive tract. The impact of this has the potential to be very high, given the high prevalence of these disorders. Indeed, there are ca. 925 million undernourished people in the world, most of them in the developing world. At the same time, the worldwide prevalence of obesity has recently doubled and 35% of adults aged 20+ (most of whom are found in developed countries) are now overweight.

3. Economy. The proposed research has the potential to foster the economic competitiveness of the UK by providing candidate intestinal drug targets for the treatment of the abovementioned disorders. British biotech companies such as Alimentary Innervations or GSK have R&D departments devoted to the development of such targets. As soon as we foresee that any of our results may have commercial implications, we will liaise with Imperial Innovations: Imperial College's technology transfer company. Services provided to academics include the identification, protection and licensing of IP; support, advice and mentoring in the creation of new companies; and provision of seed funds and links to organisations
providing further funding.