Appetite is modulated by food in the gut. Here, enteroendocrine cells sense digested nutrients and communicate the sensory signals to underlying nerves. The transmission of information between enteroendocrine cells and neurons so far has been described as indirect, via the paracrine release of hormones, because enteroendocrine cells are thought to lack synaptic contacts with nerves. This view can be largely attributed to the lack of tools to study enteroendocrine cells in vivo. We recently developed a transgenic mouse to identify enteroendocrine cells by means of fluorescence and uncover in these cells a prominent basal cytoplasmic process. We call this process a neuropod. It is through this neuropod that enteroendocrine cells connect with neurons both in vitro and in vivo as supported by preliminary data that I have produced. This is a novel sensory neurocircuit with the potential to link the lumen of the gut to the brain, and my research goal during the NIDDK Mentored Research Scientist Development Award (K01) is to characterize the function of this neurocircuit. My hypothesis is that enteroendocrine cells relay sensory information to underlying nerves through a synapse. I have assembled an innovative toolbox to characterize the function of this neurocircuit with the support of an experienced advisory committee from the Departments of Medicine and Neurobiology at Duke University. The tools include: automated 3D electron microscopy to define the ultrastructure of the connection (aim 1), a novel in vitro co-culture system of enteroendocrine cells and sensory neurons to define the electrical properties of the circuit (aim 2), and a mono-synaptic rabies virus to trace in vivo the cells of the circuit (aim 3) This research plan is expected to make a significant contribution to the understanding of gut-brain signaling and it is built within a comprehensive career development plan that will bridge my gastroenterology expertise with exceptional training in neurobiology. This 5-year career development plan will provide me with the necessary professional and scientific skills to become an independent scientist in the field of gastrointestinal sensory neurobiology.
This research-training project is relevant to public health because the enteroendocrine cell-neuron circuit has the potential to be the first node of integration between food in the gut and satiety in the brain. Understanding how food in the gut is perceived by the brain will be a foundation to develop therapeutic treatments for obesity, a disease suffered by one third of US citizens.
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