The Drosophila midgut provides a useful model for understanding the mammalian gastrointestinal tract. Great progress has been made in associating specific configurations of our gut microbial communities with distinct physiological states. Yet, precisely how enteroendocrine cells embedded in the gut epithelium sense and signal these dynamically changing microbial cues is less well understood. Our preliminary studies have laid the foundation for a powerful new Drosophila model of the enteroendocrine system. These observations raise the central hypothesis that endocrine cells signal over a long-range to control homeostasis of distant tissues.
In Aim 1 we propose to characterize the mechanism(s) by which enteroendocrine cells signal peripheral tissues.
In Aim 2 we propose to define the factors influencing luminal sensing by enteroendocrine cells. These questions are currently difficult to address in mammals, as the tools for conditionally manipulating both endocrine cell subtypes and peripheral target tissues with single cell resolution have not yet been established. Thus, we propose to use Drosophila as a model to dissect mechanisms controlling the endocrine system.
Gaining control over endocrine system function has enormous potential to impact the treatment and cure of human disease. Accurate models of how endocrine cells function in vivo are now needed to effectively develop these novel therapies. Studies in Drosophila have great predictive power for humans because of the unifying principles of biological conservation that exist at both the cellular and molecular levels.
