Pathophysiology of Transgenic Mouse Models of Huntington's Disease

亨廷顿病转基因小鼠模型的病理生理学

• 批准号: 8672693
• 负责人: Michael S. Levine
• 金额: $ 32.45万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8672693
• 关键词: Affect; Basal Ganglia; Behavioral; Cell Communication; Cells; Cerebral cortex; Complex; Corpus striatum structure; Development; Disease; Disease Progression; Equilibrium; Evaluation; Excision; Functional disorder; Funding; Gene Mutation; Genes; Genetic; Genetic Techniques; Globus Pallidus; Glutamates; Glutamine; Goals; Hereditary Disease; Huntington Disease; Impaired cognition; Intervention; Laboratories; Lead; Membrane; Motor; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Output; Pathology; Pathway interactions; Patients; Phenotype; Population; Relative (related person); Research; Resistance; Structure; Substantia nigra structure; Symptoms; Synapses; Techniques; Thalamic structure; Transgenic Mice; Trinucleotide Repeats; Work; base; design; disease phenotype; expectation; human Huntingtin protein; indexing; mouse model; mutant; novel; optogenetics; pars compacta; prevent; research study

DESCRIPTION (provided by applicant): The fatal mutation in Huntington's disease (HD) leads to an expanded glutamine repeat within the huntingtin protein which causes neuronal dysfunction typically followed by selective neurodegeneration especially within the striatum and cortex. These dysfunctions in neurons and circuits occur during the development of the disease phenotype, well before there is significant cell loss. The experiments in this application are designed to understand the functional changes that occur in specific populations of neurons during the progression of the HD phenotype and to uncover new targets and approaches for therapies. Our working hypothesis is that the most conspicuous cellular dysfunctions leading to pathology in HD result from a combination of cell- autonomous changes and cell-cell interactions. This two-hit hypothesis implies that mutation of the gene in the cell alone may not be sufficient to cause significant dysfunction; other changes have to occur to cause symptoms of the disease, and some of these include altered intercellular synaptic interactions. Previously, we examined changes in the striatum, the cortex and corticostriatal interactions, as the cortical input is one of the two major excitatory inputs to the striatum. However, the excitatory thalamic input to the striatum may be as important as the cortical input in the HD phenotype. It is presently unclear if both thalamostriatal and corticostriatal pathways contribute equally or differentially to alterations in striatal neurons. Aim 1 will use optogenetics to specifically and separately activate striatal glutamatergic inputs to identified subpopulations of striatal neurons and determine their relative contribution to cellular alterations. Medium-sized spiny neurons of the direct and indirect striatal output pathways also display unique, selective and complex alterations as the HD phenotype progresses. These will affect their targets in globus pallidus and substantia nigra. To our knowledge, striatal outputs in HD have not been studied in any detail, especially in mouse models, yet they are extremely important because they determine how the basal ganglia influence the thalamus and cortex. Aim 2 will specifically examine alterations in striatal output target structures while Aim 3 will manipulate striatal output pathwas differentially in an attempt to counter the imbalance of direct and indirect pathways as the disease progresses. Our studies use state-of-the-art optogenetic techniques to specifically activate or inhibit subclasses of neurons as well as genetic techniques to remove expression of the mutant huntingtin gene in subclasses of neurons. Together, the studies will provide the basis for novel and rational treatments for HD by delineating more restricted targets spatially and temporally and will be relevant for understanding other CAG triplet repeat diseases and neurodegenerative disorders.

描述（由申请人提供）：亨廷顿病（HD）中的致命突变导致亨廷顿蛋白内谷氨酰胺重复的扩大，这导致神经元功能障碍，通常随后发生选择性神经变性，特别是在纹状体和皮质内。这些神经元和回路功能障碍发生在疾病表型的发展过程中，早在细胞大量损失之前。本申请中的实验旨在了解 HD 表型进展过程中特定神经元群体发生的功能变化，并发现新的治疗靶点和方法。我们的工作假设是，导致 HD 病理的最明显的细胞功能障碍是细胞自主变化和细胞间相互作用共同作用的结果。这种两次打击假说意味着，仅细胞内基因突变可能不足以引起显着的功能障碍。必须发生其他变化才能引起该疾病的症状，其中一些变化包括细胞间突触相互作用的改变。之前，我们研究了纹状体、皮质和皮质纹状体相互作用的变化，因为皮质输入是纹状体的两个主要兴奋性输入之一。然而，在 HD 表型中，纹状体的兴奋性丘脑输入可能与皮质输入一样重要。目前尚不清楚丘脑纹状体和皮质纹状体通路是否对纹状体神经元的改变有相同或不同的贡献。目标 1 将使用光遗传学来特异性地、单独地激活纹状体谷氨酸输入，以识别纹状体神经元的亚群，并确定它们对细胞改变的相对贡献。随着 HD 表型的进展，直接和间接纹状体输出通路的中等大小的棘神经元也表现出独特的、选择性的和复杂的改变。这些将影响其苍白球和黑质的目标。据我们所知，HD 中的纹状体输出尚未得到任何详细研究，尤其是在小鼠模型中，但它们极其重要，因为它们决定基底神经节如何影响丘脑和皮质。目标 2 将专门检查纹状体输出目标结构的变化，而目标 3 将差异化地操纵纹状体输出路径，以试图对抗疾病进展时直接和间接路径的不平衡。我们的研究使用最先进的光遗传学技术来特异性激活或抑制神经元亚类，并使用遗传技术来消除神经元亚类中突变亨廷顿基因的表达。总之，这些研究将通过在空间和时间上描绘更受限的目标，为 HD 的新颖和合理的治疗提供基础，并将与理解其他 CAG 三联体重复疾病和神经退行性疾病相关。