Mechanisms of intestinal innervation and vascularization

As the human body's first barrier to the outside world, the digestive tract plays an essential role in breaking down food, absorbing nutrients and providing a first line of defence against harmful bacteria. Two complex systems ensure that all these important functions are adapted to the needs of our body: the nervous system, which controls the contractions and secretions of the gut, and the vascular system, which delivers oxygen to its cells. Abnormal oxygen supply and/or the malfunction of gut nerves can lead to prevalent and, sometimes life-threatening conditions, such as intestinal ischemia, Hirschsprung's disease and irritable bowel syndrome. These conditions underscore the importance of the interaction between the nervous, vascular and digestive systems. They also highlight the need to understand how these three systems interact normally, and what happens when things go wrong. This research proposal aims to identify the molecules that ensure the normal interaction between the three systems. In particular, we want to understand how nerve cells and the branches that make up the vascular system manage to find and make contact with the gut, and whether the nervous and vascular systems talk to one another to achieve this goal. Understanding how this process occurs normally will help us understand what goes wrong when nerve cells and the vascular system fail to connect to the gut properly. For example, it may well be that the molecules we identify are not present in the conditions mentioned above. In that case, we could devise ways to deliver them to patients to promote the formation of new connections between their digestive tract and their nerve cells and/or vasculature.

Internal organs are crucial regulators of metabolic and physiological homeostasis. Their functions are tightly regulated by two remarkably complex and plastic systems: a diverse network of autonomic neurons and the vasculature (a highly branched system of interconnected vessels that delivers oxygen and nutrients to all the metabolically active tissues in the body). By focusing on the digestive tract, one of the most profusely innervated and vascularized internal organs, this proposal will investigate the mechanisms that underlie the innervation and vascularization of internal organs. Our work will make use of genetic and molecular techniques in Drosophila melanogaster which allow unprecedented control of gene expression with temporal and spatial resolution. With these methods, we will be able to test the requirement for receptors and ligands in the interaction between three different tissues: a defined subset of hingdut-innervating neurons, the fly digestive tract and the visceral branches of trachea (a system of interconnected vessels developmentally and functionally analogous to the mammalian vascular system). The identification of molecules that direct axons and vasculature to the gut will open up the field of visceral axon guidance which, in contrast to the sensory and motor fields, remains largely uncharacterized. More importantly, and given that both metabolic and inflammatory conditions result from defective innervation and/or oxygen supply of the digestive tract, the genes and pathways we identify may become candidate drug targets for the treatment of disorders such as irritable bowel syndrome, Hirschsprung's disease and mesenteric ischemia.

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

1. Culture. By learning about our research and findings, members of the general public will increase their awareness of the utility of fruit flies as model systems for biomedical research. This will be achieved through two main kinds of activities:

i) Hands-on activities implemented within the framework of the Cambridge Science Festival. This 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 nervous, digestive and vascular systems of flies and humans and the importance of the crosstalk between systems. To convey the latter fact, we will use reagents (e.g. fly mutants) and images (e.g. confocal stacks of digestive tracts) generated as a result of the proposed research. These activities will help bridge the gap between scientists and the general public by making basic research accessible and allowing the public to meet the people behind the science. They will be implemented throughout the funding period and will be updated to better reflect our results.

ii) The development of documentaries/audio slideshows in collaboration with the BBC and UK film makers. These visual media will convey the medical significance and evolutionary conservation of the crosstalk between the nervous, vascular and digestive systems, and will contribute to the nation's creative output by providing an interface between science and the arts. The concept of interconnected systems of branching nerve cells and oxygen-filled tubes reaching and affecting the function of all our internal organs will be evocative and visually compelling. Contact with the relevant BBC media professionals has already been established, and interaction with documentary makers will take place during the Sheffield DocFest in 2012. This will ensure the timely delivery of any creative endeavours.

2. Health. Although this project is concerned with the normal interaction between the nervous, vascular and digestive systems, it has the potential to identify genes and pathways which could become drug targets for the treatment of metabolic disorders involving the digestive tract, such as intestinal ischemia, Hirschsprung's disease or irritable bowel syndrome. The impact of this has the potential to be very high, given the high prevalence (currently 10% for irritable bowel syndrome in the UK) and the poor prognosis (25-30% mortality in the case of Hirschsprung's and 30-73% for those affected by ischemia) of these disorders.

3. Economy. The proposed research has the potential to foster the economic competitiveness of the UK by providing candidate 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 Cambridge Enterprise: the University of Cambridge 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.