Proper weight management mandates consistent consumption of nutritionally balanced diets. Consumption of diets insufficient in amino acids leads to weight loss, muscular atrophy and generalized malaise. As such, animals rapidly reject diets lacking amino acids in search for dietary alternatives. Lysine is the most commonly limited amino acid in foods and recent reports demonstrated that rapid detection of this essential amino acid occurs via the vagus nerve. However, the vagus nerve does not have direct access to digested products of food and require signaling from cells that do. My co-sponsor's laboratory has discovered sensor cells in the intestine that synapse with neurons, now known as neuropod cells. Neuropod cells signal through neurotransmitters, and it has recently been proposed that serotonin signaling from neuropod cells quickly conveys salient cues from within the intestine. My preliminary data show that the vagus nerve can rapidly detect lysine and some intestinal sensor cells specifically sense lysine. Building upon these findings, my central hypothesis is that intestinal neuropod cells transduce onto vagal neurons the presence of essential amino acids through serotonin. To test this, two aims are proposed: (1) to test if neuropod cells are necessary for rapid vagal sensing of lysine, and (2) to determine if neuropods cells release serotonin to signal the presence of the essential amino acid lysine. I will incorporate technologies from intestinal epithelial biology and neurobiology to address these aims. In vitro assays will test the interaction between neuropod cells and vagal neurons in lysine sensing as well as serotonin release from neuropod cells following lysine administration. In vivo electrophysiology will determine the importance of neuropod cells (when combined with optogenetics) and serotonin (when combined with pharmacology) in vagal sensing of intestinal lysine. These studies are expected to uncover whether vagal sensing of the essential amino acid lysine occurs through neuropod cell release of serotonin. This proposal will ultimately support my training to become an independent physician- scientist at the intersection of gastroenterology and neurobiology research. My training plan includes presenting my findings at both local and international conferences and planning a career in translational research through structured meetings with my mentoring team as well as formal interviews with leading gut- brain scientists. With the support of this F30, I will develop the requisite skill set to successfully transition into my post-doctoral training.

Public Health Relevance

Proper nutrition is necessary to prevent and combat metabolic diseases; however, fundamental knowledge on how the body senses and determines the nutritive content of meals is not well understood. This proposal aims to identify how a dietary amino acid essential for health is sensed in the gut and signaled to the brain. Careful study of this pathway will promote new methods to treat diseases resistant to current nutritional recommendations.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZDK1)
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Densmore, Christine L
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Duke University
Internal Medicine/Medicine
Schools of Medicine
United States
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