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PhIP-induced neurodegeneration: mechanisms and relevance to Parkinson's disease

PhIP 诱导的神经变性：机制及其与帕金森病的相关性

基本信息

批准号：
8792389
负责人：
Jason R Cannon
金额：
$ 7.7万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-17 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8792389
关键词：
2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]pyridine Address Affect Amines Attention Behavior Behavioral Blood - brain barrier anatomy Bradykinesia Brain region C57BL/6 Mouse Carcinogens Cell Nucleus Chronic Clinical Trials Consumption Corpus striatum structure DNA Data Development Dietary Factors Disadvantaged Disease Disease model Dopamine Dose Environmental Risk Factor Epidemiologic Studies Experimental Designs Exposure to Freezing Goals Health Heterocyclic Amines Human In Vitro Lead Lesion Link Lipids Meat Midbrain structure Modeling Motor Mus Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurologic Neurons Neurotransmitters Parkinson Disease Pathology Pathway interactions Pesticides Posture Preparation Prevention Process Proteins Publishing Radiolabeled Rattus Reporting Research Rodent Role Serotonin Solvents Specificity System Testing Therapeutic Time Toxic effect alpha synuclein cell type cooking dopamine system dopamine transporter dopaminergic neuron feeding gamma-Aminobutyric Acid genetic risk factor in vivo member motor deficit nervous system disorder neurochemistry neurotoxicity novel oxidative damage radiotracer success therapeutic target toxicant uncooked

项目摘要

DESCRIPTION (provided by applicant): The causes of most Parkinson's disease (PD) cases are unknown (~90% are "sporadic"), while ~10 % are due to purely inherited factors. Environmental factors have long been suspected, but no toxicant has been convincingly identified. Numerous diverse classes of compounds, including pesticides and solvents have been linked to PD. This proposal tests the hypothesis that: exposure to the heterocyclic amine, 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine (PhIP), a known carcinogen in rodents, replicates key features of human Parkinson's disease (PD). Currently, there are little preliminary data on the neurological effects of chronic PhIP. However, four key factors have led to proposing a role for PhIP in PD-relevant neurodegeneration. 1) A preliminary study from members of our group showing PD-relevant motor deficits in mice 2) Published dopaminergic effects of structurally related heterocylic amines in rats 3) Potential for high-level human consumption. PhIP is the most abundant amino-imidazoazaarene isolated from the crust of cooked meat (up to 15ug/kg uncooked meat) and 4) PhIP and PhIP metabolites cross the blood-brain barrier and, therefore, may have direct effects on distinct neuronal nuclei. The major goals of this proposal are to: 1) Determine if chronic administration of PhIP in the rat reproduces the key features of PD and 2) Identify potential mechanisms of toxicity using in vitro approaches. In this proposal, the following aims will be carried out: Aim 1. To determine if chronic PhIP administration replicates the key features of PD. Aim 2. To identify mechanisms of neurotoxicity of PhIP using a primary midbrain culture system. Success of this proposal would lead to at least three major advances in PD research. 1. Identification of a possible causative factor. PhIP is a common toxicant produced in meat preparation and may be consumed in single high doses and chronically vs. most rarely encountered dopaminergic toxicants. Success of this proposal would likely prompt epidemiological studies. Further, alterations in meat preparation are available, reducing PhIP formation and a potential PD-relevant exposure. 2. Development of a new PD model. There are numerous PD models, each with advantages/ disadvantages. None have adequately considered dietary factors. Current models have also failed to predict clinical trial successes and a novel model may prove to be more successful. 3. New PD mechanisms. If PhIP exposure reproduces the key PD features, mechanistic studies would be expected to identify novel pathogenic pathways that may be therapeutic targets. In summary, using both in vivo and in vitro systems we will carefully characterize neurodegeneration after PhIP exposure and preliminarily identify mechanisms of toxicity relevant to effects on the nigrostriatal dopamine system.

描述（由申请人提供）：大多数帕金森病（PD）病例的原因是未知的（约90%是“散发性”），而约10%是由于纯粹的遗传因素。环境因素一直被怀疑，但没有令人信服的有毒物质已被确定。许多不同类别的化合物，包括杀虫剂和溶剂，都与PD有关。该提案检验了以下假设：暴露于杂环胺，2-氨基-1-甲基-6-苯基咪唑[4，5-B]吡啶（PhIP），一种已知的啮齿动物致癌物，复制了人类帕金森病（PD）的关键特征。目前，关于慢性PhIP对神经系统影响的初步数据很少。然而，四个关键因素导致提出了PhIP在PD相关神经退行性变中的作用。1)我们小组成员的一项初步研究显示了小鼠中PD相关的运动缺陷2）已发表的结构相关杂环胺在大鼠中的多巴胺能效应3）高水平人类消耗的潜力。PhIP是从熟肉的外壳中分离的最丰富的氨基-咪唑并氮杂芳烃（高达15 μ g/kg生肉）和4）PhIP和PhIP代谢物穿过血脑屏障，因此，可能对不同的神经元核具有直接作用。本提案的主要目标是：1）确定大鼠长期给予PhIP是否能繁殖 PD的关键特征和2）使用体外方法确定潜在的毒性机制。在本提案中，将实现以下目标：目标1。确定长期PhIP给药是否复制PD的关键特征。目标2.利用原代中脑培养系统鉴定PhIP的神经毒性机制。这一提议的成功将导致PD研究至少有三个重大进展。1.确定可能的致病因素。PhIP是肉类加工中产生的一种常见毒物，可能以单次高剂量和慢性消耗，而不是最罕见的多巴胺能毒物。这一提议的成功可能会促进流行病学研究。此外，肉类制备的改变是可用的，减少PhIP形成和潜在的PD相关暴露。2.开发新的PD模型。有许多PD模型，每个模型都有优点/缺点。没有人充分考虑饮食因素。目前的模型也未能预测临床试验的成功，一种新的模型可能会更成功。3.新的PD机制。如果PhIP暴露再现了关键的PD特征，则预计机制研究将确定可能成为治疗靶点的新致病途径。总之，使用体内和体外系统，我们将仔细表征PhIP暴露后的神经变性，并初步确定与黑质纹状体多巴胺系统的影响相关的毒性机制。