The role of G-protein coupled receptor kinase 2 in mucosal inflammation
G-protein coupled receptor kinases (GRKs) are a family of protein kinases comprised of seven serine/threonine kinases that were initially identified for their ability to phosphorylate G-protein coupled receptors (GPCRs). Furthermore, it has recently become evident that individual GRKs can interact in a kinase dependent or independent manner with non-receptor substrates and influence a variety of physiological functions and pathologies. This study focuses on the family member GRK2. GRK2 is expressed ubiquitously throughout the body and in addition to phosphorylating and regulating GPCR function, GRK2 is able to phosphorylate and/or interact with a large interactome of cellular proteins in a tissue - and context - specific manner. This combination of canonical and non- canonical roles of GRK2 is now attributed to a multitude of vital physiological functions including: cell migration, proliferation, metabolism, angiogenesis, and insulin resistance. This vast array of influence makes GRK2 a popular target of study for both diagnostic opportunities as well as therapeutic interventions and while GRK2 has been extensivelystudied in cardiac and immune cells its role in the intestine and the intestinal epithelium is not well understood.Inflammatory bowel disease is characterized by damage to the intestinal epithelial barrier resulting in increased permeability and the resultant dissemination of the commensal microbiota. This translocation of the luminal contents into the lamina propria constantly stimulates the immune system leading to its hyper-activation and eventual damage to the intestine. Inflammatory bowel disease is associated with increases in inflammatory cytokine production, namely TNFα and this study was performed to investigate the regulation of GRK2 on TNFα signaling in the intestinal epithelial cells and in a larger context its role in the regulation in onset and pathogenesis of acute colitis. We found that decreasing the levels of GRK2 in human epithelial cells influenced the induction of ROS production by TNFα that influences ERK1/2 signaling and the production of MMP9 to influence wound closure both in culture and in animal models. Furthermore, mice heterozygous for GRK2 were markedly protected from the onset and pathogenesis of acute DSS-induced colitis in the absence of any alterations in immune infiltration. Myeloid specific knockout studies showed this population to be in part responsible for the protection seen in the whole body knockout. Together these studies suggest that GRK2 may serve as a novel therapeutic option for the treatment of colitis.
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- In Collections
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Electronic Theses & Dissertations
- Copyright Status
- Attribution 4.0 International
- Material Type
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Theses
- Authors
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Steury, Michael
- Thesis Advisors
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Parameswaran, Narayanan
- Committee Members
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McCabe, Laura
Rockwell, Cheryl
Olson, L. Karl
Gulbransen, Brian
- Date
- 2017
- Program of Study
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Physiology - Doctor of Philosophy
- Degree Level
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Doctoral
- Language
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English
- Pages
- xiv, 168 pages
- ISBN
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9780355086379
0355086379
- Permalink
- https://doi.org/doi:10.25335/z1rr-5k47