Genetic Susceptibility Loci in Mouse Neurotoxic Parkins*

小鼠神经毒性 Parkins 的遗传易感性位点*

• 批准号: 6625904
• 负责人: Eric K Richfield
• 金额: $ 10.23万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-11 至 2003-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6625904
• 关键词: Parkinson's disease; disease /disorder onset; dopamine; environmental exposure; gene environment interaction; gene expression; genetic polymorphism; genetic susceptibility; genetically modified animals; genotype; laboratory mouse; linkage mapping; methylphenyltetrahydropyridine; neurotoxicology; neurotoxins; paraquat; phenotype; psychomotor function; quantitative trait loci; substantia nigra

DESCRIPTION (provided by applicant) The cause(s) of idiopathic Parkinson's disease (PD) in man remains unknown, but reflects an individual's combined risks associated with genetic background, life-long environmental exposures and age. The role of genotype in contributing to PD varies depending on the presence of a genetic mutation or a polymorphism that contributes to the alteration of a gene product or function. The role of the environment in idiopathic PD also varies from strong for certain neurotoxicants such as MPTP to weaker for pesticides and heavy metals. The interaction between genetic and environmental risk factors in man and mouse is poorly understood. Mouse models of PD based on genetic manipulations, neurotoxicant exposure or combined genetic and neurotoxicant exposures are useful for exploring mechanisms of neuronal loss and dysfunction. Recent breakthroughs in several areas of genetics and biotechnology will help define the roles of genes and neurotoxicants in PD. We will map Quantitative Trait Loci (QTL) in mice that play a role in mouse models of PD. We will measure baseline locomotor activity, striatal dopamine and metabolite levels, and total substantia nigra pars compacta (SNpc) neuron number in 15 inbred strains of mice treated with saline or with MPTP, paraquat, or paraquat plus maneb. We will use the association mapping procedure and mouse single nucleotide polymorphism (SNP) database created by Peltz and colleagues to map QTL for these traits in the absence or presence of a neurotoxicant. We will use permutation tests to generate appropriate experiment-wise thresholds for declaring a QTL significant. We propose a novel and innovative method for mapping QTL contributing to the adverse effects of environmental neurotoxicants resulting in the PDP in mice. Mapping of QTL will ultimately lead to a variety of studies in mice resulting in the identification of the specific genes involved and their mechanism of action in contributing to PD. Our ultimate goal is to identify specific genes, their polymorphisms, and how they interact with the environment in predisposing man to PD.

描述（由申请人提供） 人类特发性帕金森病（PD）的病因尚不清楚，但 反映了个人与遗传背景相关的综合风险， 终身环境暴露和年龄。基因型的作用 根据基因突变或多态性的存在， 导致基因产物或功能改变的基因。的作用 特发性PD中的环境也从强到弱变化， 神经毒物如MPTP对农药和重金属的毒性较弱。的 人类和小鼠遗传和环境风险因素之间的相互作用， 不太了解。 基于遗传操作、神经毒物暴露或 遗传和神经毒物的联合暴露有助于探索 神经元损失和功能障碍的机制。最近在几个方面取得的突破 遗传学和生物技术领域将有助于定义基因的作用， 神经毒素我们将绘制小鼠的数量性状基因座（QTL）， 在小鼠PD模型中发挥作用。我们将测量基线自发活动， 纹状体多巴胺和代谢物水平以及总黑质部 用生理盐水处理的15个近交系小鼠的腹侧（SNpc）神经元数目 或与MPTP、百草枯或百草枯加代森锰混配。我们将利用协会 作图程序和小鼠单核苷酸多态性（SNP）数据库 由Peltz及其同事创建，用于在不存在或 神经毒素的存在。我们将使用排列测试来生成 用于宣布QTL显著的适当的实验方面的阈值。 我们提出了一种新的和创新的方法来定位QTL有助于 环境神经毒物的不良影响导致小鼠PDP。 QTL的定位最终将导致在小鼠中的各种研究， 在识别所涉及的特定基因及其机制中， 有助于PD。我们的最终目标是确定特定的基因， 它们的多态性，以及它们如何与环境相互作用， 呼叫警局