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Principal Investigator: Michael Aschner
Organization: ALBERT EINSTEIN COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $599,412
Funding agency: National Institute of Environmental Health Sciences
PROJECT SUMMARY
Methylmercury (MeHg) is a potent neurotoxin affecting both the developing and mature central nervous system
with apparent indiscriminate disruption of multiple homeostatic pathways. However, genetic and environmental
modifiers contribute significant variability to neurotoxicity associated with human exposures. Furthermore,
neurotoxic outcomes show evidence of persistence and latent effects long after exposure has subsided. MeHg
neurotoxicity is associated with oxidative stress and impaired redox homeostasis, mitochondrial dysfunction,
activation of cell stress pathways, alteration of proteostasis, calcium dysregulation, damage to neuronal
processes and neuronal/synaptic dysfunction, to name a few. Though, these same pathological hallmarks are
seen with exposure to many (perhaps even most) neurotoxicants and underlie degenerative and developmental
disorders. Hence, while they serve as key outcomes of MeHg exposure and indicators of neurological damage,
their connection to underlying targets of MeHg neurotoxicity and inter-relationships between each other are
unknown. Compelling evidence identifies both dopaminergic (DAergic) and glutamatergic (GLUergic) neurons
as targets of MeHg-induced persistent neurotoxicity. Here we seek to identify and understand persistent and
latent effects of MeHg toxicity on biological pathways impacted by MeHg toxicity. Our goal is to understand the
toxicological hierarchy and temporal susceptibility of key toxic outcome pathways and their perpetuation. This
proposal leverages innovative technologies and the unique resources of its investigative team to build a highly
translatable and mechanistic approach. The genetically tractable Caenorhabditis elegans (C. elegans) model
system is ideally suited for discovering genetic and molecular mechanisms associated with neurotoxicity. The
human induced pluripotent stem cell (hiPSC) model enables assessment of human genetic/pharmacological
modifiers influencing neurotoxic outcomes and susceptibility along the ontogeny of defined neural lineages. Our
overarching hypothesis is that persistent effects of MeHg are self-perpetuating via interdependent relationships
of key biological pathways that sustain and regulate neurological function. We propose three aims, with each
utilizing C. elegans and hiPSC neuronal models of DAergic and GLUergic neurons, to yield a highly
complementary and robust scientific approach. To address the overarching hypothesis we have designed three
highly meritorious Specific Aims, namely (1) to evaluate the temporal pattern of persistent and latent MeHg
neurotoxicity following early and/or late developmental exposures by unbiased gene expression analysis, (2) to
test the hypothesis that the latency periods and severity of persistent neurotoxic effects of MeHg are dependent
on exposure timing, duration and total levels, and (3) to test the hypothesis that the latent/persistent effects of
MeHg exposure on biological pathways are interrelated and inexorable.
Terms: <Address><Affect><Antioxidants><Autoregulation><Behavioral><Biologic Models><Biological><Biological Models><Bread><C elegans><C. elegans><C.elegans><CNS Nervous System><Caenorhabditis elegans><Calcium><Cell Communication and Signaling><Cell Signaling><Cellular Stress><Cellular Stress Response><Central Nervous System><Classification><Consumption><Controlled Study><Coupled><Data><Degenerative Disorder><Development><Dose><Dysfunction><Environmental Factor><Environmental Risk Factor><Exposure to><Faeroe Islands><Faroe Islands><Fluorescence Activated Cell Sorting Fractionation><Fluorescence-Activated Cell Sorting><Fluorescence-Activated Cell Sortings><Functional disorder><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Generalized Growth><Genetic><Genetic Diversity><Genetic Variation><Glutamates><Goals><Growth><Homeostasis><Human><Human Genetics><Impairment><Incidence><Individual><Induced Neurons><Induced pluripotent stem cell derived neurons><Intracellular Communication and Signaling><Iraq><L-Glutamate><Metabolic><Methyl Mercury Compounds><Methylmercury Compounds><Model System><Modeling><Modern Man><Molecular><Molecular Target><Morbidity><Morbidity - disease rate><Names><Nerve Cells><Nerve Unit><Nervous System Injuries><Nervous System Physiology><Nervous System Trauma><Nervous System damage><Neural Cell><Neuraxis><Neurocyte><Neurologic Models><Neurologic Signs><Neurologic function><Neurological Damage><Neurological Injury><Neurological Models><Neurological function><Neurological trauma><Neuron from iPSC><Neuron from induced pluripotent stem cells><Neurons><Neurotoxins><New Zealand><Outcome><Outcome Measure><Oxidation-Reduction><Oxidative Stress><Pathologic><Pathway interactions><Patients><Pattern><Physiological Homeostasis><Physiopathology><Predisposition><Process><Proteins><Quality Control><R-Series Research Projects><R01 Mechanism><R01 Program><RNA Seq><RNA sequencing><RNAseq><Redox><Research><Research Grants><Research Project Grants><Research Projects><Research Resources><Resources><Role><Severities><Seychelles><Signal Transduction><Signal Transduction Systems><Signaling><Susceptibility><Symptoms><Synapses><Synaptic><System><Systematics><Testing><Therapeutic><Tissue Growth><Toxic effect><Toxicities><Toxicology><Transcript Expression Analyses><Transcript Expression Analysis><Work><adverse consequence><adverse outcome><analyze gene expression><behavior outcome><behavioral outcome><biologic><biological signal transduction><cell stress><degenerative condition><degenerative disease><design><designing><developmental><developmental disease><developmental disorder><environmental risk><experiment><experimental research><experimental study><experiments><exposed human population><gene expression analysis><gene expression assay><gene manipulation><genetic manipulation><genetically manipulate><genetically perturb><glutamatergic><healthy aging><healthy human aging><hiPSC><human exposure><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><iNeuron><iPS neurons><iPSC derived-neurons><induced human pluripotent stem cells><induced pluripotent stem cell neurons><innovative technologies><measurable outcome><methylmercury><methylmercury exposure><mitochondrial dysfunction><name><named><naming><nervous system function><neural><neuron toxicity><neuronal><neuronal toxicity><neurons derived from induced pluripotent stem cells><neuroprotection><neuroprotective><neuropsychiatric><neuropsychiatry><neurotoxic><neurotoxicant><neurotoxicity><neurotrauma><novel><ontogeny><outcome measurement><oxidation reduction reaction><pathophysiology><pathway><pharmacologic><pleiotropic effect><pleiotropism><pleiotropy><prevent><preventing><progenitor cell model><progenitor model><protein homeostasis><proteostasis><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><stem and progenitor cell model><stem cell based model><stem cell derived model><stem cell model><success><synapse><transcriptional profiling><transcriptome sequencing><transcriptomic sequencing>