Cell Signaling and Neurodegeneration

细胞信号传导和神经变性

• 批准号: 8838265
• 负责人: Harry T. Orr
• 金额: $ 45.01万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8838265
• 关键词: Adaptor Signaling Protein; Address; Affect; Aging; Alleles; Atrophic; Biology; Brain Stem; Brain region; Cerebellar Ataxia; Cerebellar Diseases; Cerebellar cortex structure; Cerebellum; Characteristics; Complex; Deglutition; Disease; Dissection; Equilibrium; Generations; Glutamine; Goals; Health; Human; Impaired cognition; Inherited; Late-Onset Disorder; Mediating; Mediator of activation protein; Motor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Onset of illness; Pathogenesis; Pathology; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Play; Post-Translational Protein Processing; Proteins; Purkinje Cells; Regulation; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Speech; Stretching; Symptoms; Therapeutic Intervention; Trinucleotide Repeats; Type 1 Spinocerebellar Ataxia; Work; ataxin-1; base; cellular targeting; effective therapy; in vivo; mutant; polyglutamine; protein complex; small hairpin RNA; therapeutic development

DESCRIPTION (provided by applicant): Spinocerebellar ataxia type 1 (SCA1) is one of nine fatal inherited neurodegenerative diseases caused by expansion of an inframe CAG trinucleotide repeat. Each repeat tract encodes a stretch of glutamine residues in the affected protein, in the case of SCA1 the protein is ataxin-1 (ATXN1). Symptoms of SCA1 include loss of motor coordination and balance, slurred speech, swallowing difficulty, spasticity, and some cognitive impairment. A characteristic feature of SCA1 pathology is atrophy and eventual loss of Purkinje cells from the cerebellar cortex. Like many neurodegenerative disorders, SCA1 is typically a late onset disease suggesting that physiological changes due to aging contribute to the onset of the disease. There is currently no effective treatment. Thus, identifying signaling pathways and cellular mediators of SCA1 onset and progression remain a application for continued support. The major aims of this competitive renewal, are: 1) dissecting the signaling pathway(s) and their components that regulate phosphorylation of ATXN1-S776 in cerebellar Purkinje cells in vivo, and 2) assessing whether S776 and its phosphorylation plays a role in mutant ATXN1-induced disease in regions of the brain in addition to Purkinje cells. Most notably the Bulbar signs affecting swallowing, due to pathology in the brainstem

描述（由申请人提供）：1型脊髓脑性共济失调（SCA1）是九个致命的遗传神经退行性疾病之一，原因是侵袭性CAG cag trinucleotide重复的扩展引起的。在SCA1的情况下，每个重复的道编码受影响蛋白质中的谷氨酰胺残基，蛋白为ataxin-1（ATXN1）。 SCA1的症状包括运动协调和平衡的丧失，语音含糊，吞咽困难，痉挛和某些认知障碍。 SCA1病理学的一个特征是萎缩和最终来自小脑皮层的Purkinje细胞丧失。像许多神经退行性疾病一样，SCA1通常是一种晚期发作疾病，表明由于衰老而导致的生理变化会导致疾病的发作。目前没有有效的治疗方法。因此，识别SCA1发作和进展的信号通路和细胞介质仍然是持续支持的应用。 The major aims of this competitive renewal, are: 1) dissecting the signaling pathway(s) and their components that regulate phosphorylation of ATXN1-S776 in cerebellar Purkinje cells in vivo, and 2) assessing whether S776 and its phosphorylation plays a role in mutant ATXN1-induced disease in regions of the brain in addition to Purkinje cells.最值得注意的是，由于脑干的病理，影响吞咽的鳞茎迹象