Exposure to high concentrations of Manganese (Mn) can cause irreversible neuronal injury in both adults and children associated with neurobehavioral, motor and cognitive deficits. Our laboratory previously demonstrated using mouse models that inflammatory changes in glial (brain) cells as a result of Mn exposure during development lead to increased susceptibility to neurological dysfunction later in life. Gram-negative bacterial infections from food poisoning, gingivitis and periodontitis are common and can also have severe neurological sequelae, including meningitis, due to circulating levels of endotoxin (lipopolysaccharide/LPS). However, it is not known why infection in some patients progresses to chronic encephalitis and neurodegeneration, whereas other patients recover. It is thought that a background of exposure to heavy metals such as Mn may elevate the risk for more severe neuroinflammatory responses to infection due to increased activation of the inflammatory transcription factor, NF-?B. Thus, the central hypothesis of this proposal is that juvenile exposure to Mn potentiates susceptibility to neuroinflammation caused by endotoxin exposures later due to NF-?B- dependent signaling in glial cells that promotes neurodegeneneration and neurological dysfunction in the basal ganglia and other affected brain regions. The following specific aims will test this hypothesis:
Specific Aim 1 - Determine the role of NF-?B in modulating the neuroinflammatory and neurodegenerative effects of Mn and LPS during development and aging. ;
Specific Aim 2 - Determine cellular interactions between astrocytes and microglia that potentiate the effects of Mn and LPS on NF-?B-dependent inflammatory signaling and neuronal injury. Achieving the goals of these aims will help to identify environmental exposures, such as heavy metals found in diet and bacterial infection. This would enable effective preventative measures for such progressive and incurable disorders.
The cause of most cases of neurodegenerative disease such as Parkinson's and Alzheimer's remains unknown, although environmental exposures are increasingly implicated as risk factors. This research is relevant to public health, because it's pursuing multiple environmental exposures as a potential for cause. Being able to identify the environmental exposures, such as heavy metals found in diet and bacterial infection, would enable effective preventative measures for such progressive and incurable disorders.
| Popichak, Katriana A; Afzali, Maryam F; Kirkley, Kelly S et al. (2018) Glial-neuronal signaling mechanisms underlying the neuroinflammatory effects of manganese. J Neuroinflammation 15:324 |
| Afzali, Maryam F; Popichak, Katriana A; Burton, Lindsey H et al. (2018) A novel diindolylmethane analog, 1,1-bis(3'-indolyl)-1-(p-chlorophenyl) methane, inhibits the tumor necrosis factor-induced inflammatory response in primary murine synovial fibroblasts through a Nurr1-dependent mechanism. Mol Immunol 101:46-54 |
| Popichak, Katriana A; Hammond, Sean L; Moreno, Julie A et al. (2018) Compensatory Expression of Nur77 and Nurr1 Regulates NF-?B-Dependent Inflammatory Signaling in Astrocytes. Mol Pharmacol 94:1174-1186 |
