Enteric Glial Cell Dysregulation of Oxidative Balance Contributes to Enteric Neuron Loss in Inflammation

Michigan State University, East Lansing MI

Investigators

Abstract

The enteric nervous system (ENS) is a heterogeneous neuronal network that lines the gut and controls intrinsic gastrointestinal (GI) function. Excitatory and inhibitory neurogenic signaling controls smooth muscle contractions and relaxations respectively, regulating the process of peristalsis. Selective loss of inhibitory motor neurons disrupts the balance of contractions and relaxations and creates permanent impairments in gut motility in functional gastrointestinal disorders like inflammatory bowel disease (IBD) and Irritable Bowel Syndrome (IBS). Yet, the exact mechanisms that contribute to this neuropathy are still unclear. Oxidative stress in the ENS is a key factor associated with enteric neuron death in intestinal and is regulated by enteric glial cells; a unique class of peripheral glia that surround and support and maintain the neuronal extracellular environment. My central hypothesis is that a combination of high glial nitric oxide (oxidant) production and/or low glial glutathione (antioxidant) production contributes to neuron death during inflammation. We will test this hypothesis in two specific aims. Specific Aim 1 will determine the mechanisms that regulate glial NO during intestinal inflammation. Specific Aim 2 will determine how changes in glial glutathione (GSH) production contribute to enteric neurodegeneration during intestinal inflammation. In investigating these aims, I will generate transgenic mouse models using viral knockdowns, and use immunohistochemistry, live-cell fluorescent imaging and in vivo and in situ models of enteric neuron loss to understand the mechanisms of glial oxidative balance regulation. Understanding the role of glial cells in regulating oxidative balance during intestinal inflammation will identify novel molecular targets for the development of therapeutics for GI disorders.