Current Research Projects
Enteric corticotropin-releasing factor (CRF) and stress
My recent studies have focused on the role of enteric CRF and CRF receptors in regulation of gut motility, secretion, and epithelial barrier function. CRF is a brain-gut peptide known to be involved in stress-evoked symptoms of diarrhea, cramping, abdominal pain and fecal urgency, which are hallmarks of diarrhea-predominant irritable bowel syndrome (d-IBD), infectious enteritis, food allergy, and inflammatory bowel disease (IBD) in humans. Psychogenic stress evokes and exacerbates the symptoms of d-IBS and IBD. Previous studies focused on the role of central CRF (i.e. CRF in the hypothalamus) in stress-related gut dysfunction. The gut itself has CRF and it receptors. However, the role of enteric CRF and CRF receptors in maintaining normal gut function, and their role in stress-related gut dysfunction are still not clear. This project aims to understand how release of CRF in the enteric nervous system during stress are transformed into symptoms of cramping abdominal pain, fecal urgency and watery diarrhea. It will: (1) determine which of the neuronal phenotypes in the enteric nervous system express CRF and CRF receptors; (2) explain the cellular neurophysiology underlying CRF-mediated excitation in musculomotor, secretomotor, and vasculomotor neurons and interneurons in the enteric nervous system; (3) test for CRF-induced plasticity of neurotransmission in the enteric nervous system; (4) test for acute and chronic stress-induced upregulation of CRF or CRF receptors in the enteric nervous system; (5) test the effects of knocking-down CRF or CRF receptor expression by in vivo RNA interference on normal gut function and responses to acute and chronic stress. Results of this project are expected to shed light on therapeutic targeting of CRF receptors in functional gastrointestinal and inflammatory disorders.
Transient receptor potential channel in excitatory neurotransmission in the enteric nervous system
This project is designed to understand better the cellular neurobiology of synaptic signaling in secretomotor neurons in the submucosal plexus of the enteric nervous system. Synaptic inputs to secretomotor neurons are known to have an essential role in neuronal control of intestinal secretion in normal and disordered states. We recently identified a novel slow excitatory postsynaptic potential (EPSP) in the submucosal secretomotor neurons that is mediated by the purinergic P2Y1 receptors. This purinergic slow EPSP has proved to be important in regulating secretomotor neuron excitability and intestinal fluid secretion. The molecular nature of the ion channel(s) responsible for the changes in membrane potential during the purinergic slow EPSP is not known. The specific hypothesis to be tested is that members of the canonical transient receptor potential (TRPC) channel mediate the purinergic slow EPSP in the submucosal secretomotor neurons. This hypothesis is based on the following observations: (1) The P2Y1-mediated slow EPSP has a reversal potential near 0 mV, which is similar to the reversal potentials of the TRPC channels expressed in heterologous systems. (2) The TRPC channels are activated by phospholipase C (PLC)-coupled receptors. It is well documented that the P2Y1 receptor is coupled to PLC. (3) The non-selective TRP channel blockers, SKF96365 and 2-APB, suppress the P2Y1 receptor-mediated slow EPSP (preliminary observations). (4) Pilot/feasibility studies find that submucosal secretomotor neurons express TRPC1, TRPC4 and TRPC6. Based on these observations, the experiments outlined in this proposal will: (1) test the hypothesis that the purinergic slow EPSP in submucosal secretomotor neurons is mediated by opening of TRPC channels; (2) identify the TRPC subunits that are involved in purinergic neurotransmission; 3) identify the intracellular signal transduction mechanisms that lead to the activation of native TRPC channels in intestinal submucosal secretomotor neurons. Our long-term goals are to establish the role of TRPC channels in mucosal secretory responses evoked by purinergic P2Y1 receptor activation and enteric neuronal reflexes.
Effects of hibernation on the enteric nervous system
This project is designed to understand the effects of hibernation on the expression of neurotransmitters in the enteric nervous system using the thirteen-lined ground squirrel as a model.