Transgenic Mouse Models of Huntington's Disease

亨廷顿病转基因小鼠模型

• 批准号: 6640426
• 负责人: Michael S. Levine
• 金额: $ 32.6万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6640426
• 关键词: Huntington's disease; calcium flux; corpus striatum; disease /disorder model; electrophysiology; gene expression; gene mutation; genetically modified animals; glutamate receptor; laboratory mouse; lethal genes; nerve /myelin protein; neurons; neuropathology; polymerase chain reaction; polynucleotides; protein structure function; synapses; voltage /patch clamp

DESCRIPTION (provided by applicant): This proposal will examine cellular mechanisms underlying the dysfunctions detected in Huntington's disease (HD) using four different murine models. The lethal mutation in HD produces an expanded trinucleotide (GAG) repeat within the protein huntingtin. It causes selective neurodegeneration especially in the striatum and cortex, by an unidentified mechanism. Each of the HD models we will examine exhibits a different phenotype produced by unique transgene constructs or 'knocked-in" GAG repeat lengths. By evaluating multiple models we will be able to examine the dysfunctions in more detail and understand the specificity and sequence of physiological changes common to HD and the models. Based on our preliminary studies, we have uncovered several common cellular deficits in two models. These are enhanced responsiveness of N-methyl-D-aspartate (NMDA) receptors in the striatum associated with increased Ca2+ flux, a marked decrease in K+ conductances and a change in the corticostriatal synaptic response. A third model also displays the enhanced response to NMDA. Some of these changes potentially predispose striatal medium-sized spiny neurons to excitotoxic damage. Using a physiological approach, we will examine four hypotheses concerning the cellular mechanisms of dysfunction in HD: 1) alterations in ionotropic glutamate receptor function and changes in evoked and spontaneous excitatory synaptic inputs to striatal neurons 2) alterations in metabotropic glutamate and dopaminergic receptor modulation of ionotropic glutamate receptor function, 3) alterations in K+ conductances and 4) alterations in Ca2+ conductances. The precise onset of changes will be investigated in relationship to the expression of behavioral deficits by using animals that are presymptomatic or after development of overt motor signs. We will examine striatal and corticostriatal neurons, visualized in the slice preparation or acutely dissociated cells, to characterize basic functions by current- and voltage-clamp analyses. Because HD destroys so many different capabilities - intellectual, physical and emotional - the insights gained from this research elucidating the cellular malfunctions in HD are relevant to understanding other GAG repeat disorders and neurological diseases associated with protein aggregate pathologies like Alzheimer's and Parkinson's disease.

描述（由申请人提供）：该提案将检查使用四种不同的鼠模型在亨廷顿氏病（HD）中检测到功能障碍的基础机制。 HD中的致命突变在蛋白质亨廷汀内重复产生扩展的三核苷酸（GAG）。它引起选择性神经退行性的，尤其是在纹状体和皮质中，通过未识别的机制。我们将检查的每一个HD模型都会展示由独特的转基因构建体或“敲入”重复长度产生的不同表型。通过评估多个模型，我们将能够详细检查功能障碍，并更了解与HD和模型相同的生理变化的特异性和序列。根据我们的预测研究，我们可以在几个模型中脱离了两个模型，这些模型具有两种模型，这些模型具有这些模型，这些模型具有这些模型。与Ca2+通量增加的纹状体中的N-甲基-D-天冬氨酸（NMDA）受体，K+电导率明显减少，皮质层状突触响应的变化也会显示出对纹状体中等的刺激性疾病，也会显示出增强的NMDA。涉及HD中功能障碍的细胞机制：1）离聚谷氨酸受体功能的改变以及引起和自发性兴奋性突触输入的变化对纹状体神经元2）变化2）改变型谷氨酸和甲状腺激素受体调节的变化，并改变了型甲状腺激素受体调节。 Ca2+电导的改变。通过使用预示性的动物或在明显的运动体征发展后，将研究与行为缺陷表达的关系的确切变化开始。我们将检查在切片制备或急性分离的细胞中可视化的纹状体和皮质纹状体神经元，以通过电流和电压夹分析来表征基本功能。由于HD破坏了许多不同的能力 - 智力，身体和情感 - 从这项研究中获得的见解阐明了HD中的细胞故障与了解其他与Alzheimer和Parkinson疾病（如蛋白质骨料病理学）相关的其他GAG重复疾病和与蛋白质聚集的病理学相关的神经系统疾病有关。