Mn element toxicity12/28/2023 This hypothesis will be tested by three Specific Aims that will examine: the role of glial- specific NF-kB activation in promoting Mn-induced neurotoxicity during development and aging (Specific Aim 1), critical cell-cell interactions between astrocytes and microglia necessary for amplifying inflammatory activation and neuronal injury (Specific Aim 2), and transcriptional regulatory mechanisms in astrocytes mediating NF-kB-dependent induction of neuroinflammatory genes (Specific Aim 3). ![]() It is the central hypothesis of this proposal that Mn exposure during development stimulates NF-kB-dependent intercellular signaling between microglia and astrocytes, resulting in ongoing neuroinflammation that enhances susceptibility to neurological dysfunction during aging. Persistent inflammatory changes in glial cells may b a potential link between exposure to Mn early in life and heightened susceptibility to neurotoxic injury and neurological dysfunction during aging because neuroinflammation is now recognized as a central feature in the progression of manganism and other neurological disorders of the basal ganglia. Children appear to be more vulnerable to Mn than adults and recent epidemiological evidence links high Mn in drinking water to cognitive and behavioral impairment in children but the basis for the apparent greater sensitivity of young individuals is not clear. ![]() ![]() Exposure to elevated levels of the essential element manganese (Mn) causes a spectrum of neurochemical and neuropathologic changes that can culminate in irreversible neuronal injury in subcortical and cortical structures. Neurotoxic injury to the developing CNS is linked to neurological disease in humans but mechanisms that may predispose to such conditions remain very poorly understood.
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