Repeat associated neurodegeneration in CANVAS

CANVAS 中重复相关的神经变性

基本信息

批准号：
10536010
负责人：
Peter K Todd
金额：
$ 42.49万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10536010
关键词：
Ataxia Atrophic Autopsy Basal Ganglia Biological Assay Brain region CRISPR/Cas technology Cells Cerebellar Ataxia Cerebellar Diseases Cerebellar degeneration Complex DNA Transposable Elements Defect Development Diffuse Disease Disease Progression Disease model Drosophila genus Elements Exhibits Face Genes Genetic Goals Human Impairment Induced pluripotent stem cell derived neurons Inheritance Patterns Inherited Introns Lead Length Modeling Molecular Morbidity - disease rate Nerve Degeneration Neurons Neuropathy Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Pentanucleotide Repeats Peptides Peripheral Pluripotent Stem Cells Poly(A) Tail Population Prosencephalon Proteins Purkinje Cells RNA Reporter Sensory Syndrome System Technology Testing Therapeutic Toxic effect Translating Translations Trigeminal System Work base cerebral atrophy effective therapy gain of function induced pluripotent stem cell loss of function mortality neuron loss neuronal survival neurotoxicity novel sensory neuropathy somatosensory therapeutic target tool transcriptome

项目摘要

Abstract: Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late-onset, slowly progressive and recessively inherited ataxia characterized by vestibular, cerebellar, and somatosensory impairments and cerebellar degeneration that results in significant morbidity and early mortality. CANVAS is caused by a biallelic, non-reference, pentameric AAGGG repeat expansion within the second intron of replication factor complex subunit 1 (RFC1) gene in both familial and sporadic CANVAS, as well as a significant fraction of all late-onset degenerative ataxias and sensory neuronopathies. Controls possess an average of 11 AAAAG repeats at this locus, which is replaced with between 400-2000 AAGGG repeats in CANVAS patients. The mechanism(s) by which this repeat expansion causes neurodegeneration are unknown. While CANVAS exhibits a recessive pattern of inheritance, studies to date suggest that RFC1 expression is not impacted by the repeat expansions. The expansion has the potential to be pathogenic within two different strand-specific contexts. On the sense strand, the (AAGGG)n repeat sits within the poly(A) tail of an AluSx3 transposable element, while the antisense strand (CCCTT)n repeat sits within the large second intronic region of RFC1. The goal of this proposal is to define the mechanisms by which these repeat elements contribute to neurodegeneration in CANVAS. To accomplish this, we will use a combination of patient-derived iPSC models alongside studies using repeat-expressing reporters to investigate the expanded repeat within both its endogenous context as well as within easily manipulable assay systems that will allow us to define the potential of these repeat elements to elicit toxicity directly. Taken together, these studies will provide critical information needed to define the proximal mechanism(s) and pathways that underlie neuronal toxicity and neurodegeneration within CANVAS – a critical first step required for development of disease relevant therapeutics.

抽象的：小脑性共济失调伴神经病和前庭无反射综合征 (CANVAS) 是一种迟发性、缓慢的疾病以前庭、小脑和体感为特征的进行性和隐性遗传性共济失调损伤和小脑变性导致显着的发病率和早期死亡率。由复制的第二个内含子内的双等位基因、非参考、五聚体 AAGGG 重复扩增引起家族性和散发性 CANVAS 中的因子复合体亚基 1 (RFC1) 基因，以及很大一部分所有迟发性退行性共济失调和感觉神经病对照平均具有 11 AAAAG。在 CANVAS 患者中，该基因座被 400-2000 个 AAGGG 重复序列取代。尽管 CANVAS 表现出这种重复扩张导致神经退行性变的机制尚不清楚。隐性遗传模式，迄今为止的研究表明 RFC1 表达不受重复序列的影响扩展有可能在两个不同的特定链环境中产生致病性。有义链中，(AAGGG)n 重复序列位于 AluSx3 转座元件的 Poly(A) 尾内，而反义链 (CCCTT)n 重复序列位于 RFC1 的第二大内含子区域内。提案是定义这些重复元件导致神经退行性变的机制为了实现这一目标，我们将结合使用源自患者的 iPSC 模型和研究。使用重复表达生产者来研究其内源环境中的扩展重复就像在易于操作的分析系统中一样，这将使我们能够定义这些重复元件的潜力总而言之，这些研究将提供定义近端毒性所需的关键信息。 CANVAS 内神经元毒性和神经变性的机制和途径——一个关键开发疾病相关疗法所需的第一步。