Bioregulation Group (BRG)
Understanding and manipulating the immune system, inflammation, and bone physiology will lead to more effective treatment of numerous conditions, including infectious diseases, chronic viral infection, chronic inflammatory diseases (arthritis, endodontic infection, and periodontitis), autoimmune diseases (multiple sclerosis and insulin-dependent diabetes), metabolic bone diseases (osteoporosis), abnormal craniofacial development and cancer. Cell surface receptors linked to cytosolic cell signaling systems activate transcription factors for expression of secreted cytokines of immune, inflammatory and bone cells in order to regulate the immune system, inflammation, bone-turnover and tissue repair. To understand cytokine secretion important for regulation of biological processes, the BRG examines receptors, cell signaling pathways, genes, promoter sequences, and associated transcription factors. The BRG is also involved in discovery of novel compounds that are natural or synthetic that antagonize or agonize these pathways and, thus, more predictably could be used to improve inflammatory, immune and bone responses.
The research endeavors of the Bioregulation Research Group (BRG) address several human disease problems:
1. Beneficial bone remodeling caused by controlled tooth movement (orthodontics)
2. Alveolar bone resorption (periodontitis), dental pulp necrosis (endodontics), and neurological dysfunction (multiple sclerosis) brought about by chronic inflammation, dysfunctional immune responses, or exhausted immune responses during persistent bacterial, fungal, or viral infections.
3. Immune modulating virulence factors produced by microbes that could cause chronic inflammation, persistent infection, and excessive bone resorption. These factors include lipopolysaccharide and other pathogen-associated molecules derived from bacteria; farnesol, a virulence factor derived from the fungus Candida albicans; and L- and L* protein produced by the Cardioviruses.
In vitro protocols used by the BRG involve:
1. Cytokines: While an understanding of cytokine production can be obtained using harvested tissues and exudates from specific microenvironments, a mechanistic understanding of regulation and modulation of these cytokines can be done in vitro using immune, inflammatory, and bone cells in culture.
2. Pharmaceuticals that can modulate these cytokines are first tested in vitro. These pharmaceuticals include resveratrol, a phytoestrogen derived from plant foods such as red grapes, non-antibacterial tetracyclines, such as subantimicrobial doxycycline (which is approved for human use and has been tested in human clinical trials at the UNMC College of Dentistry), and the cholesterol-lowering drug, simvastatin, which has novel bone-augmenting properties.
In vivo rodent model protocols used by the BRG include:
1. Theiler’s murine encephalomyelitis virus (TMEV) causes a chronic viral infection that leads to neuroinflammatory disease similar to Multiple Sclerosis in some strains of mice. We investigate innate immune system factors responsible for chronic TMEV infections in susceptible mice and compare these responses to resistant mice.
2. Experimental autoimmune encephalomyelitis (EAE) in mice is another model of human Multiple Sclerosis. We bring about EAE by injecting myelin proteins derived from the white matter of the central nervous system into mice. We evaluate anti-inflammatory agents (e.g., resveratrol) on neurological dysfunction brought about by chronic viral infection or EAE.
3. Experimental bone growth in the bilateral rat mandible can measure excessive bone resorption/remodeling that can occur due to chronic microbial infection near bone, such as periodontal disease (periodontitis). We examine the effects of topical drugs (e.g., simvastatin) on bone growth in a bilateral rat mandible model of periodontitis.