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）中的致死性突变导致亨廷顿蛋白内谷氨酰胺重复序列扩增，导致神经元功能障碍，通常随后发生选择性神经变性，尤其是在纹状体和皮质内。神经元和回路的这些功能障碍发生在疾病表型的发展过程中，远在有显著的细胞损失之前。本申请中的实验旨在了解HD表型进展期间特定神经元群体中发生的功能变化，并发现新的治疗靶点和方法。我们的工作假设是，导致HD病理学的最明显的细胞功能障碍是由细胞自主变化和细胞-细胞相互作用的组合引起的。这种两次打击假说意味着细胞中的基因突变可能不足以引起显著的功能障碍;必须发生其他变化才能引起疾病的症状，其中一些包括细胞间突触相互作用的改变。在此之前，我们研究了纹状体，皮质和皮质纹状体的相互作用的变化，因为皮质输入是纹状体的两个主要兴奋性输入之一。然而，兴奋性丘脑输入纹状体可能是一样重要的皮质输入HD表型。目前尚不清楚丘脑纹状体和皮质纹状体通路是否同样或不同地影响纹状体神经元的改变。目的1将使用光遗传学来特异性地和单独地激活纹状体神经元的识别亚群的纹状体神经元能输入，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型多刺神经元也显示出独特的、选择性的和复杂的改变。这些将影响他们在苍白球和黑质的目标。据我们所知，尚未对HD的纹状体输出进行任何详细研究，特别是在小鼠模型中，但它们非常重要，因为它们决定了基底神经节如何影响丘脑和皮质。目标2将具体检查纹状体输出靶结构的改变，而目标3将差异地操纵纹状体输出通路，以试图对抗疾病进展时直接和间接通路的不平衡。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的亚类，以及遗传技术来去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多限制性靶点，为HD的新型和合理治疗提供基础，并将与理解其他CAG三联重复疾病和神经退行性疾病相关。