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）：大多数帕金森氏病（PD）病例的原因尚不清楚（约90％是零星的），而约10％是由于纯粹遗传的因素。长期以来，人们一直怀疑环境因素，但没有令人信服地确定有毒物质。包括农药和溶剂在内的许多不同类别的化合物与PD有关。该提案检验了以下假设：暴露于杂环胺，2-Amino-1-甲基-6-苯基咪唑[4,5-B]吡啶（PHIP），啮齿动物中已知的致癌物，复制人类帕金森氏病（PD）的关键特征。当前，关于慢性PHIP的神经系统作用的初步数据很少。但是，四个关键因素导致提出了PHIP在PD相关神经变性中的作用。 1）我们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）在大鼠中发表了与结构相关的杂环胺的多巴胺能作用3）高水平人类消费的潜力。 PHIP是从煮熟的肉（最多15盎司/千克未煮过的肉）中分离出的最丰富的氨基氨基唑唑唑唑唑唑唑，4）PHIP和PHIP代谢物穿过血脑屏障，因此可能直接对不同的神经元核产生直接影响。该提案的主要目标是：1）确定大鼠中PHIP的长期给药是否会重现 PD的关键特征和2）使用体外方法确定毒性的潜在机制。在此提案中，将执行以下目标：目标1。确定慢性PHIP给药是否复制PD的关键特征。目标2。使用原发性中脑培养系统确定PHIP神经毒性的机制。该提案的成功将导致PD研究的至少三个重大进步。 1。鉴定可能的因子因子。 PHIP是在肉类制剂中产生的一种常见有毒物质，可以用单一的高剂量和长期遇到的多巴胺能有毒物质食用。该提案的成功可能会促使流行病学研究。此外，还可以改变肉类制剂，减少PHIP的形成和潜在的与PD相关的暴露。 2。开发新的PD模型。有许多PD模型，每种模型都有优势/缺点。没有人充分考虑饮食因素。当前的模型也未能预测临床试验成功，新型模型可能被证明更成功。 3。新的PD机制。如果PHIP暴露再现了关键的PD特征，则预计机械研究将确定可能是治疗靶标的新型致病途径。总而言之，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，并初步识别与对黑质纹状体多巴胺系统作用相关的毒性机制。