Reflex behaviors of the intestine including peristalsis are orchestrated by the enteric nervous system (ENS); a complex neural network embedded in the gut wall. Inflammation profoundly alters ENS circuits controlling motility by promoting enteric ganglionitis; an inflammatory neuropathy characterized by the death of enteric neurons. Neuropathy is increasingly recognized as a trigger for persistent gut dysfunction in gastrointestinal (GI) motility and functional bowel disorders but the mechanisms that regulate neuropathy are not understood. This proposal investigates the role of enteric glial cells, astrocyte-like cells that surround neurons in the ENS, in the regulation of enteric neuropathy. The proposed studies will use in vivo models of GI inflammation, transgenic mice, immunohistochemistry, live-cell imaging with fluorescent probes, biosensing assays and functional tests to study neuron-glia interactions. The central hypothesis is that purinergic activation of enteric glial cells differentially regulates neuron survival depending on glial activation by ADP or adenosine. There are 2 specific aims in this proposal, each with three sub-aims.
Each aim will link in vitro mechanistic studies in tissue from humans and mice with in vivo functional studies in transgenic mice.
Aim 1 will test the hypothesis that glial Ca2+ responses driven by ADP cause reactive gliosis, neuron death and gut dysfunction.
Specific aim 1 A will test how activation of glial Ca2+ responses in GFAP:hM3Dq mice or human tissue transduced with glial- specific vectors affects the induction of reactive gliosis and neuron death.
Aim 1 B wil test whether glial cells directly drive neuron death by releasing neurotoxic substances or if glial driven neuron death requires immune cell recruitment. Mice with an inducible ablation of connexin-43 or MHC-II in glia will be used to specifically interfere with gliotransmitter release o immune cell recruitment, respectively.
Aim 1 C will test how manipulation of gliosis using the transgenic mice listed above affects in vivo and ex vivo intestinal function.
Aim 2 will test the hypothesis that adenosine inhibits reactive gliosis and stimulates protective mechanisms in glia to preserve ENS function.
Aim 2 A will use drugs and CD73 null mice to test if activation of glial adenosine receptors is necessary and/or sufficient to reverse reactive gliosis.
Aim 2 B will test whether the neuroprotective actions of glial A2BR activation are mediated by altering the release of glial mediators or by decreasing the inflammatory infiltrate following in vivo inflammation in CD73 null mice.
Aim 2 C will use in vivo inflammation, drugs and CD73 null mice to determine how manipulation of glial adenosine signaling impacts in vivo and ex vivo assays of gut function following acute inflammation. Significance: Intestinal inflammation can drive enteric neuropathy, leading to persistent gut dysfunction in GI motility disorders. Understanding how glial mechanisms both promote, and limit enteric neuropathies is important because it could lead to the discovery of novel therapeutic targets and a common causative mechanism of neuron death in GI motility disorders, functional bowel disorders and inflammatory bowel disease.
The manifestation of gastrointestinal (GI) motility and functional bowel disorders is caused, in part, by alterations to the function or survival of neuron that control GI muscle. The proposed studies investigate how the glial cells that surround these neurons drive neuronal dysfunction. A detailed understanding of the role of enteric glia will lead to new therapies to treat GI motility and functional bowel disorders.
|Gulbransen, Brian D; Christofi, Fievos L (2018) Are We Close to Targeting Enteric Glia in Gastrointestinal Diseases and Motility Disorders? Gastroenterology 155:245-251|
|Feldbrügge, Linda; Jiang, Z Gordon; Csizmadia, Eva et al. (2018) Distinct roles of ecto-nucleoside triphosphate diphosphohydrolase-2 (NTPDase2) in liver regeneration and fibrosis. Purinergic Signal 14:37-46|
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|Jiang, Z Gordon; Sandhu, Bynvant; Feldbrügge, Linda et al. (2018) Serum Activity of Macrophage-Derived Adenosine Deaminase 2 Is Associated With Liver Fibrosis in Nonalcoholic Fatty Liver Disease. Clin Gastroenterol Hepatol 16:1170-1172|
|Brown, Isola A M; Gulbransen, Brian D (2018) The antioxidant glutathione protects against enteric neuron death in situ, but its depletion is protective during colitis. Am J Physiol Gastrointest Liver Physiol 314:G39-G52|
|Fried, David E; Watson, Ralph E; Robson, Simon C et al. (2017) Ammonia modifies enteric neuromuscular transmission through glial ?-aminobutyric acid signaling. Am J Physiol Gastrointest Liver Physiol 313:G570-G580|
|Grubiši?, Vladimir; Gulbransen, Brian D (2017) Enteric glial activity regulates secretomotor function in the mouse colon but does not acutely affect gut permeability. J Physiol 595:3409-3424|
|Savio, Luiz Eduardo Baggio; de Andrade Mello, Paola; Figliuolo, Vanessa R et al. (2017) CD39 limits P2X7 receptor inflammatory signaling and attenuates sepsis-induced liver injury. J Hepatol 67:716-726|
|McClain, Jonathon L; Gulbransen, Brian D (2017) The acute inhibition of enteric glial metabolism with fluoroacetate alters calcium signaling, hemichannel function, and the expression of key proteins. J Neurophysiol 117:365-375|
|Mahnke, Karsten; Useliene, Jurgina; Ring, Sabine et al. (2017) Down-Regulation of CD62L Shedding in T Cells by CD39+ Regulatory T Cells Leads to Defective Sensitization in Contact Hypersensitivity Reactions. J Invest Dermatol 137:106-114|
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