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Mechanisms of PhIP-induced dopaminergic neurotoxicity

PhIP 诱导多巴胺能神经毒性的机制

基本信息

批准号：
10595271
负责人：
Jason R Cannon
金额：
$ 156.34万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10595271
关键词：
2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]pyridine Address Animal Model Autophagocytosis Biochemical Biological Models Brain Cell model Cells DNA Adduction DNA Adducts DNA Damage Data Data Set Disease Disease model Domestic Fowls Dopamine Environment Exhibits Fishes Genes Genomic DNA Grant Histological Techniques Human Impairment Link Literature Meat Mediating Mitochondria Mitochondrial DNA Mitochondrial Proteins Modeling Molecular Monophenol Monooxygenase Motor Nematoda Nerve Degeneration Neurons Nuclear Outcome Parkinson Disease Pathogenesis Pathologic Pathology Pathway interactions Prevalence Prevention Process Proteins Publications Rattus Research Rodent Model Role Testing Therapeutic Toxic effect Toxicology Translational Research Viral Viral Vector adduct brain metabolism cooking dietary heterocyclic aromatic amines in vivo insight metabolomics mitochondrial dysfunction nervous system disorder neuromelanin neuron loss neurotoxic neurotoxicity novel oxidative damage protein aggregation pyridine toxicant

项目摘要

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.

多巴胺(DA)-能性神经退行性变是帕金森病（PD）的病理标志