DEVELOPMENT OF CELLULAR & ANIMAL MODELS FOR HUNTINGTONS

蜂窝技术的发展

• 批准号: 6436657
• 负责人: Danilo A. Tagle
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6436657
• 关键词: Huntington's disease; artificial chromosomes; disease /disorder model; genetically modified animals; glutaminase; laboratory mouse; model design /development; molecular cloning; molecular pathology; nucleic acid repetitive sequence; protein glutamine gamma glutamyltransferase; protein structure; protein structure function; transfection

Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder with onset generally in midlife. HD is characterized by chorea, dementia, and neuropsychiatric problems. The mutation lies in the expansion of a polymorphic CAG repeat resulting in greater than normal length of polyglutamines in the N-terminal end of the HD gene product (huntingtin) which is of unknown function. We have created mouse models for HD that recapitulates features of behavioral abnormalities and neuropathological changes inherent in the human disease. These mice carrying the repeat expansions show progressive behavior going from hyperkinesia to hypokinesia and akinesia. Pathologically, neurons show early dendritic changes cumlminating in apoptotic changes and cell loss. We have identified morphological changes in affected neurons of these mice that mark early events of pathogenesis and these changes are supported independently by molecular and biochemical approaches using cDNA microarrays and immunocytochemical stains for vesicular proteins and cytoskeleton. The interplay of mutant huntingtin with these proteins and how these interactions could lead to neurodegenertaive changes are the subject of intense investigation by this group. These studies will lead to a better understanding of brain function as it relates to cognition, emotions, and neuronal survival; and may lead to better therapeutic regimens for HD and other degenerative disorders of the brain.

亨廷顿病（Huntington 'sdisease，HD）是一种常染色体显性遗传的进行性神经退行性疾病，通常在中年发病。HD的特征是舞蹈病、痴呆和神经精神问题。该突变在于多态性CAG重复序列的扩增，导致HD基因产物（亨廷顿蛋白）的N-末端中多聚谷氨酰胺的长度大于正常长度，其功能未知。我们已经创建了HD的小鼠模型，其概括了人类疾病中固有的行为异常和神经病理学变化的特征。这些携带重复扩增的小鼠表现出从运动过度到运动减退和运动不能的渐进行为。病理学上，神经元表现出早期树突状变化，最终导致凋亡变化和细胞丢失。我们已经确定了这些小鼠的受影响的神经元的形态学变化，标志着发病的早期事件，这些变化是独立的支持分子和生物化学方法，使用cDNA微阵列和免疫细胞化学染色的囊泡蛋白和细胞骨架。突变亨廷顿蛋白与这些蛋白质的相互作用以及这些相互作用如何导致神经退行性变化是该小组深入研究的主题。这些研究将导致更好地了解大脑功能，因为它与认知，情绪和神经元存活有关;并可能导致更好的治疗方案用于HD和其他大脑退行性疾病。