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：
9104730
负责人：
Jason R Cannon
金额：
$ 33.35万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9104730
关键词：
2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]pyridine Acute Address Affect American Animal Model Animals Behavior Behavioral Biochemical Biological Markers Brain Breast CYP1A1 gene Carcinogens Cells Chronic DNA DNA Adducts DNA Sequence Alteration Data Development Diet Disease Disease model Domestic Fowls Dose Environmental Risk Factor Enzymes Epidemiology Essential Tremor Etiology Event Exhibits Fishes Gene Mutation Genetic Goals High temperature of physical object Human Hydroxylation In Vitro Incidence LRRK2 gene Laboratories Laboratory Animals Lead Link Lipids Malignant Neoplasms Measurement Measures Meat Mediating Metabolism Methods Modeling Modification Motor Movement Disorders Mus Mutate Mutation N hydroxylation Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Neurotoxins Neurotransmitters Oxidative Stress Paper Parkinson Disease Pathology Pathway interactions Penetrance Pesticides Population Positioning Attribute Prevention Process Prostate Proteins Publishing Rattus Recommendation Research Role Rotenone Solvents Staging Sulfhydryl Compounds System Techniques Tertiary Protein Structure Testing Therapeutic Time Tissues Toxic Environmental Substances Transgenic Organisms Ursidae Family adduct base cooking disease-causing mutation disorder risk dopaminergic neuron experience exposed human population exposure route follow-up gene environment interaction genotoxicity heterocyclic aromatic amines in vivo in vivo Model nervous system disorder neurobehavioral neurochemistry neurotoxic neurotoxicity novel oxidation oxidative damage pre-clinical public health relevance pyridine research study success synuclein therapeutic target toxicant toxicant interaction uptake

项目摘要

DESCRIPTION (provided by applicant): The causes of most Parkinson's disease (PD) cases are unknown, ~90% are 'sporadic', ~10% are attributed to inheritance. Environmental factors, including pesticides and solvents, have long been suspected, but no toxicant has been convincingly identified. Most cases are thought to arise from gene -environment interactions. A specific example is leucine-rich repeated kinase 2 (LRRK2), a large multi-domain protein with an unknown endogenous function. Numerous LRRK2 mutations cause PD. However, incomplete penetrance in humans and heightened sensitivity to dopaminergic (DA) neuron toxicants in animals expressing mutations suggest the importance of gene-environment interactions. Mounting data from the Cannon laboratory and others suggests that heterocyclic aromatic amines (HAAs) are neurotoxic and associated with neurodegenerative diseases, including PD. HAAs have been primarily investigated as carcinogens in laboratory animals and as potential human carcinogens. HAAs are formed during high temperature meat and poultry cooking. Thus, chronic HAA exposure through diet may be much more common and occur at higher levels than for many environmental toxicants. This proposal tests the hypothesis that: 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most mass abundant HAA in cooked meats and poultry, exhibits selective dopaminergic neurotoxicity by a newly proposed mechanism of neurotoxic action through N-hydroxylation, a metabolite in common with PhIP's mediated genotoxicity. Our data suggests that mechanistic studies on PhIP neurotoxicity are critical to understanding a potential role in PD. The major goals of this proposal are to: 1) Characterize PhIP-mediated neurotoxicity in vivo; 2) Determine if PhIP exposure potentiates pathology in animals expressing mutated (G2019S) LRRK2 (the most common genetic cause of PD); 3) Identify key mechanism(s) of PhIP-mediated DA-selective neurotoxicity through examination of whether N-hydroxylation is a key pathogenic event, and by assessing the propensity of N-oxidized PhIP metabolites to broadly form adducts with major biomolecules. Modifications and adduct formation in specific PD-implicated proteins will also be examined. Success of this project will lead to several major advances. 1) Identification of a possible causative factor: PhIP is a common toxicant produced in cooked meats and may be consumed in higher doses than rarely encountered known DA toxicants; 2) Creation of a new gene-environment interaction model utilizing the most common PD causing-mutation and a compound to which humans are widely exposed; 3) New PD mechanisms: mechanistic studies would likely identify novel pathogenic pathways that may be therapeutic targets; 4) Prompt follow-up epidemiological and biomarker studies. In summary, using both in vivo and in vitro systems, we will carefully characterize PhIP-induced neurodegeneration and identify mechanisms of DA neurotoxicity. If PhIP exposure is proven to have a causative role in PD, then recommendations can be provided to the public because PhIP exposure can be mitigated by changes in cooking methods.

描述（由适用提供）：大多数帕金森氏病（PD）病例的原因尚不清楚，〜90％是“零星”，〜10％归因于遗传。长期以来一直怀疑包括农药和解决方案在内的环境因素，但没有令人信服地确定有毒物质。大多数情况被认为是由基因 - 环境相互作用引起的。一个具体的例子是富含亮氨酸的重复激酶2（LRRK2），这是一种具有未知内源性功能的大型多域蛋白。许多LRRK2突变引起PD。然而，人类的不完全渗透性以及表达突变的动物中对多巴胺能（DA）神经毒性的敏感性提高了基因环境相互作用的重要性。加农炮实验室和其他人的安装数据表明，杂环芳香胺（HAAS）是神经毒性的，并且与神经退行性疾病有关，包括PD。 HAA在实验动物和潜在的人类致癌物中主要研究为致癌物。在高温肉和家禽烹饪过程中形成了哈斯。这是，通过饮食暴露的慢性HAA暴露可能比许多环境有毒物质更为普遍，并且发生在更高的水平上。 This proposal tests the hypothesis that: 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the Most mass richant HAA in cooked meats and poultry, exhibits selective dopaminergic neurotoxicity by a newly proposed mechanism of neurotoxic action through N-hydroxylation, a metabolite in common with PhIP's mediated遗传毒性。我们的数据表明，关于PHIP神经毒性的机械研究对于理解PD中的潜在作用至关重要。该提案的主要目标是：1）在体内表征PHIP介导的神经毒性； 2）确定表达突变（G2019S）LRRK2（PD的最常见遗传原因）动物中的PHIP暴露潜力病理学； 3）通过检查N-羟基化是否是关键的致病事件，并通过评估N氧化的PHIP代谢物以与主要的生物分子大致形成加合物，从而确定PHIP介导的DA选择性神经毒性的关键机制。还将检查特定PD蛋白质中的修饰和加合物形成。该项目的成功将导致几个重大进展。 1）鉴定可能的严重因素：PHIP是用煮熟的肉产生的一种常见有毒物质，并且可能比很少遇到的已知DA有毒物质的剂量更高剂量； 2）使用最常见的PD引起的pd和人类广泛暴露的化合物创建新的基因环境相互作用模型； 3）新的PD机制：机械研究可能会确定可能是治疗靶标的新型致病途径； 4）迅速的随访流行病学和生物标志物研究。总而言之，使用体内和体外系统，我们将仔细地表征PHIP诱导的神经变性并确定DA神经毒性的机制。如果证明PHIP暴露在PD中具有致病作用，则可以向公众提供建议，因为烹饪方法的变化可以减轻PHIP暴露。