Understanding the Cellular Basis of Movement Disorders

了解运动障碍的细胞基础

基本信息

批准号：
10160963
负责人：
Puneet Opal
金额：
$ 53.2万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10160963
关键词：
Adult Affect Agonist Alzheimer&apos s Disease Astrocytes Ataxia Autopsy Behavior assessment Brain CAG repeat Cannabinoids Cell Proliferation Cells Cerebellar degeneration Cerebellum Data Defect Development Developmental Process Disease Disease Progression Electrophysiology (science)Event Functional disorder Genetic Genetic Transcription Human Huntington Disease Impairment Interneurons Life Light Modeling Movement Disorders Mus Myoepithelial cell Nerve Degeneration Neurodegenerative Disorders Neurons Neurotransmitters Parkinson Disease Pathogenicity Pathologic Pathology Patients Pharmacology Phenotype Plant Roots Play Population Process Proliferating Proteins Purkinje Cells Resistance Role Seizures Sonic Hedgehog Pathway System Testing Therapeutic Time Toxic effect Trinucleotide Repeat Expansion Type 1 Spinocerebellar Ataxia Wild Type Mouse ataxin-1 base behavior test cyclopamine endogenous cannabinoid system experimental study gain of function gamma-Aminobutyric Acid inhibitor/antagonist knock-down mutant network dysfunction overexpression polyglutamine postnatal preclinical trial presynaptic prevent receptor sonic hedgehog receptor stellate cell stem cell niche stem cell population stem cells therapeutic target transcriptomics transmission process

项目摘要

Project Summary Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide repeat expansion in ATXN1 that leads to an abnormally long polyglutamine tract in the subsequent protein, ataxin-1 (ATXN1). Mutant ATXN1 has a propensity to misfold, resist cellular degradation, and increase in toxicity as its levels rise. This toxicity occurs by a gain of function mechanism with evidence point to transcriptional derangements as an early, presymptomatic pathogenic event. We recently discovered that the earliest abnormalities in Purkinje cells (cells that are most vulnerable in SCA1) are not caused by cell- autonomous changes but in a non-cell autonomous manner by affecting the proliferation and fate of cerebellar post-natal stem cells. In this proposal, we will test the hypothesis that the underlying SCA1 pathology has its roots in early developmental processes and that if these defects are overcome one might be able to delay or ameliorate later neurodegeneration, thus paving the way for therapy for this currently untreatable condition.

项目概要脊髓小脑共济失调 1 型 (SCA1) 是一种由 CAG 引起的常染色体显性神经退行性疾病 ATXN1 中的三核苷酸重复扩增导致异常长的多聚谷氨酰胺束随后的蛋白质，ataxin-1 (ATXN1)。突变的 ATXN1 具有错误折叠、抵抗细胞降解的倾向，并且随着其水平的升高，毒性也会增加。这种毒性是通过功能获得机制发生的，有证据表明指出转录紊乱是一种早期的、症状前的致病事件。我们最近发现浦肯野细胞（SCA1 中最脆弱的细胞）最早的异常不是由细胞引起的通过影响小脑的增殖和命运，以非细胞自主的方式自主改变产后干细胞。在本提案中，我们将检验以下假设：潜在的 SCA1 病理学有其自身的特点根源于早期发育过程，如果克服这些缺陷，人们可能能够延迟或改善后来的神经退行性变，从而为治疗这种目前无法治疗的疾病铺平道路。