The enteric nervous system plays a critical role in normal function of the intestine. Enteric neurons provide motor and sensory information to generate propulsive movement and maintain organ homeostasis. Homeostasis in the digestive system is also maintained in part by chemical sensors present on different subtypes of enteroendocrine cells. These cells are positioned throughout the intestinal epithelium in order to aid in communicating luminal conditions to enteric neurons within the submucosa. Enteroendocrine cells secrete a variety of mediators to stimulate afferent neurons. One of the most studied of these cells are serotonin (5-HT) synthesizing enterochromaffin cells. Enterochromaffin cells (EC) store about 95% of the serotonin within vertebrates. Mechanical and nutrient stimulation of EC cells results in basal 5-HT secretion into the submucosa. 5-HT binds to numerous 5-HT receptors located on intrinsic primary afferent neurons (IPANs). IPANs synapse with interneurons and motor neurons creating peristaltic and secremotor responses. Primary afferent extrinsic neurons on the other hand communicate with the CNS to create visceral sensation. 5-HT is charged at physiological pH and must be removed by transport across cellular membranes using the serotonin transporter (SERT). Alteration of components of the intestinal serotonin signaling system is associated with digestive diseases including Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), and celiac disease. IBS is a common disorder with altered motility, secretion, and visceral sensation within the intestine for which there is no specific biological markers. We will investigate the role of the serotonin signaling system to determine how it functions within the zebrafish digestive system.
Specific aim 1 will further identify how enteroendocrine cells are specified within the intestinal epithelium with an emphasis on enterochromaffin cells as well as modification of serotonin signaling components.
Specific aim 2 will correlate changes in motility and with real time in vivo measurements of 5-HT within the embryonic zebrafish intestine after alteration of 5-HT signaling components.
This research will contribute to identification of mechanisms by which motility of the digestive tract is acquired. When neurotransmitters critical to motility are disrupted, diseases such as Irritable Bowel Syndrome, Inflammatory Bowel Disease, and celiac disease develop. Genetic defects identified in this research will contribute to understanding these conditions.
