Mechanisms of PhIP-induced dopaminergic neurotoxicity
Mechanisms of PhIP-induced dopaminergic neurotoxicity
批准号:
10595271
负责人:
Jason R Cannon
金额:
$156.34万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-09-15 至 2026-08-31
关键词:
2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]pyridineAddressAnimal ModelAutophagocytosisBiochemicalBiological ModelsBrainCell modelCellsDNA AdductionDNA AdductsDNA DamageDataData SetDiseaseDisease modelDomestic FowlsDopamineEnvironmentExhibitsFishesGenesGenomic DNAGrantHistological TechniquesHumanImpairmentLinkLiteratureMeatMediatingMitochondriaMitochondrial DNAMitochondrial ProteinsModelingMolecularMonophenol MonooxygenaseMotorNematodaNerve DegenerationNeuronsNuclearOutcomeParkinson DiseasePathogenesisPathologicPathologyPathway interactionsPrevalencePreventionProcessProteinsPublicationsRattusResearchRodent ModelRoleTestingTherapeuticToxic effectToxicologyTranslational ResearchViralViral Vectoradductbrain metabolismcookingdietaryheterocyclic aromatic aminesin vivoinsightmetabolomicsmitochondrial dysfunctionnervous system disorderneuromelaninneuron lossneurotoxicneurotoxicitynoveloxidative damageprotein aggregationpyridinetoxicant
中文摘要
多巴胺(DA)-能性神经退行性变是帕金森病(PD)的病理标志
英文摘要
Dopamine (DA)-ergic neurodegeneration is a pathological hallmark of Parkinson’s disease (PD) that produces
the cardinal motor features. Major gaps in the literature remain on if and how common dietary exposures may
contribute to pathogenesis. This proposal aims to address these gaps through highly mechanistic studies of
neurotoxicity from dietary toxicants known as heterocyclic aromatic amines (HAAs). In the first cycle of
R01ES025750, we made major advances demonstrating that HAAs produce selective DAergic neurotoxicity in
cellular, nematode, and rodent model systems. We also identified HAA-induced oxidative damage, protein
aggregation, autophagy disruption, and DNA adduct formation as key biochemical and molecular outcomes
that are of critical importance to PD. Within this dataset, we have made overarching mechanistic advances that
set the stage for a mechanism-of-action-focused renewal. First, neuromelanin (NM) is critical to HAA
intracellular accumulation and neurotoxicity. This finding points to selectivity because NM is formed in
catecholaminergic neurons in humans, and a critical translational need for NM cell and animal models in the
study of HAAs (NM is lacking in most PD models). Second, HAAs selectively target mitochondria, again
pointing to possible selectivity because DAergic neurons are especially sensitive to mitochondrial toxicity. Based
on these data and the literature, we will test the following mechanistic hypothesis: HAA-induced DAergic
neurotoxicity is mediated through biochemical interactions between NM and mitochondrial dysfunction that
produce a neurotoxic cascade. We will test this hypothesis through three aims. In Aim 1, we will determine if
NM-forming rats exhibit heightened HAA-induced DAergic neurotoxicity. In novel, NM-forming rats, we will
assess HAA accumulation, HAA brain metabolism, and neurotoxicity to establish PD relevance. In Aim 2, we
will identify mitochondrial targets that mediate HAA-induced neurotoxicity. We will discover the role of
mitochondrial DNA adducts of HAAs in mediating neurotoxicity by quantifying adducts formed in
mitochondrial versus genomic DNA. Further, we will identify HAA bioactivation pathways that lead to
mitochondrial and genomic DNA adduct formation. Finally, we will identify specific mitochondrial gene and
protein impairments resulting from DNA damage. In Aim 3, we will demonstrate connections between NM,
mitochondrial dysfunction, and protein aggregation. Using cell-free, cellular and animal model systems, we will
determine the effects of NM on HAA-mediated perturbations of mitochondrial function, autophagy (especially
mitophagy), and the propagation of PD-relevant protein aggregation using biochemical and histological
techniques. Overall, elucidation of interactions between NM, mitophagy/autophagy, and protein aggregation as
critical to HAA neurotoxic mechanism of action is expected to significantly advance understanding of HAA-
induced neurotoxicity and, more broadly, environmentally induced DAergic neurotoxicity. These studies are
expected to significantly advance understanding of PD etiopathogenesis.
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DOI:
10.1016/j.neuro.2018.01.009
发表时间:
2018-03
期刊:
Neurotoxicology
影响因子:
3.4
作者:
[Cruz-Hernandez A, Agim ZS, Montenegro PC, McCabe GP, Rochet JC, Cannon JR]
通讯作者:
Cannon JR
DOI:
10.1002/jbt.22694
发表时间:
2021-04
期刊:
Journal of biochemical and molecular toxicology
影响因子:
3.6
作者:
[Syeda T, Cannon JR]
通讯作者:
Cannon JR
DOI:
10.1021/acs.chemrestox.1c00274
发表时间:
2022-01-17
期刊:
Chemical research in toxicology
影响因子:
4.1
作者:
[Syeda T, Cannon JR]
通讯作者:
Cannon JR
DOI:
10.1016/j.tox.2020.152436
发表时间:
2020-03
期刊:
Toxicology
影响因子:
4.5
作者:
[Tauqeerunnisa Syeda;R. Foguth;Emily Llewellyn;J. Cannon]
通讯作者:
Tauqeerunnisa Syeda;R. Foguth;Emily Llewellyn;J. Cannon
DOI:
10.1016/j.neuro.2020.10.005
发表时间:
2020-12
期刊:
Neurotoxicology
影响因子:
3.4
作者:
[Lawana V, Um SY, Foguth RM, Cannon JR]
通讯作者:
Cannon JR
PFOS-induced dopaminergic neurodegeneration across nematode, amphibian, and rodent models
-
批准号:10042289
-
项目类别:
-
资助金额:$22.4万
-
财政年份:2020
-
负责人:Jason R Cannon
-
依托单位:
PFOS-induced dopaminergic neurodegeneration across nematode, amphibian, and rodent models
-
批准号:10241311
-
项目类别:
-
资助金额:$18.52万
-
财政年份:2020
-
负责人:Jason R Cannon
-
依托单位:
PFOS-induced dopaminergic neurodegeneration across nematode, amphibian, and rodent models
-
批准号:10289079
-
项目类别:
-
资助金额:$30.85万
-
财政年份:2020
-
负责人:Jason R Cannon
-
依托单位:
Mechanisms of PhIP-induced dopaminergic neurotoxicity
-
批准号:9104730
-
项目类别:
-
资助金额:$33.35万
-
财政年份:2016
-
负责人:Jason R Cannon
-
依托单位:
PhIP-induced neurodegeneration: mechanisms and relevance to Parkinson's disease
-
批准号:8643407
-
项目类别:
-
资助金额:$7.7万
-
财政年份:2014
-
负责人:Jason R Cannon
-
依托单位:
PhIP-induced neurodegeneration: mechanisms and relevance to Parkinson's disease
-
批准号:8792389
-
项目类别:
-
资助金额:$7.7万
-
财政年份:2014
-
负责人:Jason R Cannon
-
依托单位:
New Approaches to Gene-environment Interaction Modeling in Parkinson's Disease
-
批准号:8610308
-
项目类别:
-
资助金额:$24.9万
-
财政年份:2012
-
负责人:Jason R Cannon
-
依托单位:
New Approaches to Gene-environment Interaction Modeling in Parkinson's Disease
-
批准号:8350767
-
项目类别:
-
资助金额:$24.9万
-
财政年份:2012
-
负责人:Jason R Cannon
-
依托单位:
New Approaches to Gene-environment Interaction Modeling in Parkinson's Disease
-
批准号:8424270
-
项目类别:
-
资助金额:$24.9万
-
财政年份:2012
-
负责人:Jason R Cannon
-
依托单位:
New Approaches to Gene-environment Interaction Modeling in Parkinson's Disease
-
批准号:8089751
-
项目类别:
-
资助金额:$9.0万
-
财政年份:2011
-
负责人:Jason R Cannon
-
依托单位:
海外基金