Enteric Neuroscience
Dr. Sharkey’s research is focused on understanding the physiology and pathophysiology of the the neural control of the gastrointestinal (GI) tract and brain-gut interactions in health and disease. My focus is to understand the role of the enteric nervous system in GI disorders such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) where the fundamental dual role of the gut, digestion and absorption of nutrients and host defense, becomes severely impaired. The overarching hypothesis of my research is that enteric nerves and glia synergistically interact to maintain intestinal homeostasis and perturbations in their function lead to GI disease. Digestion becomes impaired when there are abnormalities in the control of GI motility and/or a breakdown in the intestinal barrier. My program has two main aims:

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Aim 1. To understand how the endocannabinoid system (ECS) regulates GI motility. The regulation of neurotransmitter release in the ENS is important in the control of GI motility. Endocannabinoids are key molecules in this process, but the underlying mechanisms still elude us. We study the ECS in both enteric neurons and enteric glia and its role in the control of control of small intestinal and colonic motility using in vitro and in vivo techniques. We investigate the control of GI motility in animal models of disease and normal and pathologic human tissue samples. Using knowledge gained from these studies we will test novel compounds that alter components of the ECS in order to treat abnormal GI motility.

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Aim 2. To establish the role of enteric glia in the control of intestinal barrier function. My lab has shown that enteric glia are key regulators of the intestinal barrier. How enteric nerves, enteroendocrine cells and the enteric microbiota interact with enteric glia in order to effect regulatory control remains to be understood. We will examine the role of enteric glia in barrier function using genetic techniques, live cell imaging and pharmacological approaches in isolated animal tissues and mucosal biopsies from patients. We will perform in vitro and in vivo studies in animal models of disease. We will study how the gut microbiota are involved in neural regulation of secretory and barrier function in our models of GI disease.