Neuroinflammation and developmental vulnerability to manganese toxicity

描述（由申请人提供）：对发育中的中枢神经系统的神经毒性损伤与人类神经系统疾病有关，但可能导致此类疾病的机制仍然知之甚少。暴露于必需元素锰（Mn）水平升高会引起一系列神经化学和神经病理变化，最终导致皮层下和皮层结构的不可逆神经元损伤。儿童似乎比成人更容易受到锰的影响，最近的流行病学证据表明，饮用水中的高锰与儿童的认知和行为障碍有关，但年轻人明显更敏感的基础尚不清楚。神经胶质细胞的持续炎症变化可能是早期接触锰与衰老过程中神经毒性损伤和神经功能障碍易感性增加之间的潜在联系，因为神经炎症现在被认为是锰中毒和基底神经节其他神经系统疾病进展的核心特征。这是该建议的中心假设，发育期间暴露于锰刺激

DESCRIPTION (provided by applicant): 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. 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. 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. 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. 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. 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). We will use a two-hit model in NF-kB-EGFP reporter mice and astrocyte-specific NF-kB knockout mice generated in our laboratory that expose animals to Mn from pre-weaning through puberty and then examine their susceptibility to the dopaminergic neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We except to identify temporal patterns of NF-kB activation in astrocytes and microglia that correlate with onset of neuroinflammation and that astrocyte-specific loss of function of NF-kB activity will mitigate the neurotoxic effects of Mn, both in developing mice and during aging. We also expect that exposure to Mn during juvenile development will lead to greater neurological dysfunction during aging due to persistent neuroinflammation that increases neuronal dysfunction, relative to mice without prior exposure to Mn. Collectively, the proposed Specific Aims will build upon previous work from our laboratory to address key mechanistic questions regarding critical cellular interactions between astrocytes and microglia that potentiate neuronal dysfunction caused by developmental exposure to Mn.