Prenatal environmental toxicants induce neuroinflammation causing autistic behaviors
Prenatal environmental toxicants induce neuroinflammation causing autistic behaviors
批准号:
9129967
负责人:
David A Lawrence
金额:
$60.8万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-09-01 至 2021-08-31
关键词:
AddressAffectAntibodiesAntibody SpecificityAntigen-Antibody ComplexAntigensAutoimmune ProcessAxonBTBR MouseBehaviorBehavioralBindingBiological AssayBiological MarkersBiological ModelsBirthBloodBrainBrain regionCellsCharacteristicsChildCoculture TechniquesCommunicationConflict (Psychology)CoupledDevelopmentDiagnosisDiesel ExhaustEvaluationExperimental ModelsExposure toFetusFluorescenceGenesGeneticGenetic PolymorphismHumanImmuneImmunoprecipitationIndividualInflammationInflammatoryInterventionMaternal antibodyMercuric chlorideMercuryMicrogliaMouse StrainsMusMyeloid CellsNeonatalNeuronsNewborn InfantOutcomeOxidantsOxidation-ReductionOxidative StressPathway interactionsPeptidesPhenotypePlasmaPredispositionPregnancyProcessProductionReportingResearchSamplingSerumSex CharacteristicsSourceSpecificitySpottingsStructureSurfaceSynapsesTherapeutic InterventionTissuesToxic Environmental SubstancesToxicant exposureTranslationsWestern BlottingYolk Sacarmautism spectrum disorderautistic behaviourbehavior changebiosignaturecytokineexposed human populationfetalmacrophagemonocyteneonateneurobehavioralneuroinflammationneuronal circuitryoffspringparticleparticle exposurepostnatalpregnantprenatalprogenitorrelating to nervous systemresponsetoxicant
中文摘要
虽然针对大脑抗原的抗体(Abs)与ASD的发展有关,但是
英文摘要
Although antibodies (Abs) to brain antigens have been implicated in the development of ASD, and the
specificities of these Abs are beginning to be identified, there has been no direct quantification of the
mechanisms responsible for the behavioral aberrancies associated with ASD. Communication between
neurons in different brain regions requires the neurons to establish information delivery circuits with extended
arms connecting the neurons located at different distances. Interference with proper connections can affect
numerous behaviors as well as normal body functions. This study will utilize brains from mice that have ASD-
like behaviors (BTBR strain) and those with normal behavior unless exposed to altered fetomaternal influences
from toxicant exposures with HgCl2 and/or diesel exhaust particles (DEP). Prenatal Hg and DEP effects have
been reported to induce ASD-like behaviors similar to those of BTBR mice, which have anti-brain Abs and
neuroinflammation. These immune activities in the brain are posited to interfere with development of proper
neuronal connections. The hypothesis is that environmental toxicants induce a combination of fetal innate
immune cell (microglial) activities and maternal Abs to initiate a detrimental neuroinflammatory response in the
developing brain. The resultant inflammation and immune interferences with neuronal structures/functions alter
synaptic neuronal connections and functions resulting in the ASD-like behaviors of offspring. Microglia are
known to influence the development of neuronal circuits, so it is not surprising that toxicants, which can alter
immune cell phenotypes, could directly affect the type of microglia developed from yolk sac progenitors, their
distribution in the brain, and their functions in the presence of immune complexes (Abs and brain antigens).
The common specificities from mouse studies will be used to explore the Ab specificities in newborn blood of
children now known to have ASD. In the proposed study, Abs will be assayed in organotypic co-cultures of
fetal or neonatal tissue from different brain regions to quantify modulation of “neuronal connectivity”. The brain
regions will come from normal untreated mice or from brain regions of the fetuses or neonates from Hg and
DEP exposed dams ± the Abs with common specificities of experimental mice and human newborns. By
mixing the source of the mouse brain region, we will investigate if the detriment is more with the sprouting or
targeted region. The study has short-term and long-term impact on the field of ASD research. The most
immediate impact is identification of an “Ab Biosignature of ASD” that could diagnose the ASD phenotype at
birth. Another short-term impact would be delineation of the specificities and mode of action of the Abs and
microglia that identify ASD-related mechanisms, which in the long-term could aid in determining interventions
that might be most appropriate. Identification of the mechanisms detrimental to normal neuronal connectivity
and function could assist in the development of therapeutic interventions. The study also will validate the
establishment of an experimental model system to screen additional environmental toxicants.
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批准号:7849549
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批准号:7647568
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资助金额:$10.0万
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Biomarker signatures of biological, chemical, or psychological stress
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批准号:7615790
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资助金额:$0.74万
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批准号:7629783
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批准号:8072944
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资助金额:$1.46万
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批准号:7882119
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资助金额:$10.84万
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批准号:7337668
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资助金额:$47.18万
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财政年份:2007
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批准号:8144568
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项目类别:
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资助金额:$0.1万
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财政年份:2007
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负责人:David A Lawrence
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依托单位:
Neuroimmunotoxicology of mercury
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批准号:7195362
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项目类别:
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资助金额:$18.89万
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财政年份:2006
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负责人:David A Lawrence
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依托单位:
Neuroimmunotoxicology of mercury
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批准号:7514651
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项目类别:
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资助金额:$16.32万
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财政年份:2006
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负责人:David A Lawrence
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依托单位:
Immunotoxic effects of lead on cytokine expression
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批准号:6471138
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项目类别:
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资助金额:$31.85万
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财政年份:2002
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负责人:David A Lawrence
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依托单位:
Immunotoxic effects of lead on cytokine expression
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批准号:6623926
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资助金额:$27.3万
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负责人:David A Lawrence
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依托单位:
Immunotoxic effects of lead on cytokine expression
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批准号:6835655
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项目类别:
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资助金额:$35.54万
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财政年份:2002
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负责人:David A Lawrence
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依托单位:
Immunotoxic effects of lead on cytokine expression
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批准号:6702307
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项目类别:
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资助金额:$27.76万
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财政年份:2002
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负责人:David A Lawrence
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依托单位:
Immunotoxic effects of lead on cytokine expression
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批准号:6854394
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项目类别:
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资助金额:$7.3万
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财政年份:2002
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负责人:David A Lawrence
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依托单位:
TOXICOLOGY OF METAL INDUCED IMMUNOPATHOLOGY
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项目类别:
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资助金额:$15.07万
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依托单位:
海外基金