Genetic Susceptibility Loci in Mouse Neurotoxic Parkins*

描述(由申请人提供) 人类特发性帕金森氏症(PD)的病因(S)尚不清楚，但 反映了一个人与遗传背景相关的综合风险， 终生环境暴露和年龄。基因分型在基因中的作用 对帕金森病的易感性取决于基因突变或多态的存在 导致基因、产物或功能改变的。的作用 特发性帕金森病的环境也从肯定的强烈到不同 MPTP等神经毒物对农药和重金属的作用较弱。这个 人类和小鼠的遗传和环境风险因素之间的相互作用是 人们对此知之甚少。 基于遗传操作、神经毒物暴露或 基因和神经毒物的联合暴露有助于探索 神经元丢失和功能障碍的机制。最近在几个方面取得了突破 遗传学和生物技术领域将有助于定义基因和 帕金森病中的神经毒物。我们将在小鼠身上定位数量性状基因座(QTL) 在帕金森病小鼠模型中发挥作用。我们将测量基线运动活动， 纹状体多巴胺和代谢物水平，以及黑质总部 15种近交系小鼠生理盐水处理后的SNPC神经元数量 或使用MPTP、百草枯或百草枯加maneb。我们将利用协会 作图程序和小鼠单核苷酸多态(SNP)数据库 由Peltz和他的同事创建，用于定位这些性状的QTL 有神经毒剂的存在。我们将使用排列测试来生成 宣布一个QTL显著的合适的实验阈值。 我们提出了一种新颖和创新的QTL定位方法，有助于 环境神经毒物对小鼠PDP的不良影响。 QTL的定位最终将导致对小鼠的各种研究，从而 在鉴定涉及的特定基因及其机制方面 为PD作出贡献的行动。我们的最终目标是识别特定的基因， 它们的多态，以及它们如何在易感过程中与环境相互作用 警员呼叫警局。

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.