Lead (Pb2+) poisoning remains the most common disease of environmental origin in the United States today. The long-term goal is to investigate age-specific and cell type-specific mechanisms by which lead causes its neurotoxicity. Lead is known to cause myelin defects, although the mechanism is unclear. Myelin in the central nervous system is formed by oligodendrocytes, making these cells a possible target for lead. The investigators have previously demonstrated that environmentally relevant, low-level lead can disturb the survival, proliferation, and differentiation of oligodendrocytes at critical windows of development. The investigators have also demonstrated that developing oligodendrocytes are highly vulnerable to excitotoxicity mediated by Ca2+-permeable glutamate receptors (GluRs). Lead is a divalent metal ion that can mimic Ca2+ and interferes with Ca2+-sensitive targets. Mitochondria play a major role in buffering intracellular Ca2+, and are a known Pb2+ target. Here we propose to examine the hypothesis that a critical factor in lead neurotoxicity is the impairment of Ca2+-permeable GluR function and alteration of developmental GluR expression, concurrently with deficits in signaling mechanisms involving altered mitochondrial dynamics and redox potential in developing oligodendrocytes, resulting in aberrant neuron-glia connectivity and functional impairments.
Aim 1 of this proposal will examine whether Pb2+ inhibits Ca2*-permeable GluR function in developing oligodendrocytes, and determine the relative roles of GluR subtypes in Pb2+ toxicity.
Aim 2 will determine whether lead exposure modifies GluR subunit expression and phosphorylation state, and downstream signaling molecules that regulate GluR function.
Aim 3 will determine whether Pb2+ causes alterations in mitochondrial function, maturation, dynamics effusion and fission, and redox state in developing oligodendrocytes. Overall, the Principal Investigator proposes to use a combination of cellular and molecular techniques applied to both in vitro and in vivo models of lead exposure, to provide overlapping approaches to unravel novel mechanisms of lead-induced toxicity to the developing brain. This project is the first to study the role of GluRs and mitochondria of developing oligodendroglia in lead toxicity. Elucidating these previously unrecognized mechanisms of Pb2+ action will provide insights into understanding the risks associated with lead exposure and the development of intervention strategies of targeting Ca2+-permeable GluRs and associated signaling pathways for dealing with lead toxicity.
|Daugherty, Daniel J; Chechneva, Olga; Mayrhofer, Florian et al. (2016) The hGFAP-driven conditional TSPO knockout is protective in a mouse model of multiple sclerosis. Sci Rep 6:22556|
|Jiang, Peng; Chen, Chen; Liu, Xiao-Bo et al. (2016) Human iPSC-Derived Immature Astroglia Promote Oligodendrogenesis by Increasing TIMP-1 Secretion. Cell Rep 15:1303-15|
|Liu, Ying; Deng, Wenbin (2016) Reverse engineering human neurodegenerative disease using pluripotent stem cell technology. Brain Res 1638:30-41|
|Li, Shenglan; Xue, Haipeng; Wu, Jianbo et al. (2015) Human Induced Pluripotent Stem Cell NEUROG2 Dual Knockin Reporter Lines Generated by the CRISPR/Cas9 System. Stem Cells Dev 24:2925-42|
|Xiao, Juan; Liu, Wenwei; Chen, Yingyu et al. (2015) Recombinant human PDCD5 (rhPDCD5) protein is protective in a mouse model of multiple sclerosis. J Neuroinflammation 12:117|
|Chung, S-H; Biswas, S; Selvaraj, V et al. (2015) The p38? mitogen-activated protein kinase is a key regulator of myelination and remyelination in the CNS. Cell Death Dis 6:e1748|
|Xiao, Juan; Yang, Rongbing; Yang, Lin et al. (2015) Kirenol attenuates experimental autoimmune encephalomyelitis by inhibiting differentiation of Th1 and th17 cells and inducing apoptosis of effector T cells. Sci Rep 5:9022|
|Chechneva, O V; Mayrhofer, F; Daugherty, D J et al. (2014) A Smoothened receptor agonist is neuroprotective and promotes regeneration after ischemic brain injury. Cell Death Dis 5:e1481|
|Lo, U; Selvaraj, V; Plane, J M et al. (2014) p38? (MAPK14) critically regulates the immunological response and the production of specific cytokines and chemokines in astrocytes. Sci Rep 4:7405|
|Chen, Chen; Jiang, Peng; Xue, Haipeng et al. (2014) Role of astroglia in Down's syndrome revealed by patient-derived human-induced pluripotent stem cells. Nat Commun 5:4430|
Showing the most recent 10 out of 41 publications