Molecular Basis of Pathogenic Cascades in ALS/FTD Initiated from C9orf72 Hexanucleotide Repeat Expansion
C9orf72 六核苷酸重复扩增引发 ALS/FTD 致病级联的分子基础
基本信息
- 批准号:10659232
- 负责人:
- 金额:$ 62.1万
- 依托单位:
- 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:2022-07-15 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:AgingAlzheimer&aposs DiseaseAmyotrophic Lateral SclerosisBindingBiochemicalBrainC9ORF72CellsChromatinClinicalDAXX geneDNADNA BindingDNA Repeat ExpansionDNA-Binding ProteinsDefectDementiaDiseaseEIF-2alphaElderlyElementsEpigenetic ProcessEquilibriumEtiologyExpanded DNA RepeatFeedbackFoundationsFrontotemporal DementiaGene ExpressionGene Expression RegulationGenesGeneticGenetic DiseasesGenetic PolymorphismGenetic studyGenomeGenomicsGoalsHuman GenomeHuntington DiseaseHybridsInterventionKnowledgeLinkMediatingMicrosatellite RepeatsModelingMolecularMotor NeuronsMutationNerve DegenerationNeurodegenerative DisordersNeuromuscular DiseasesNuclearNuclear ProteinNucleotidesPathogenesisPathogenicityPathologyPathway interactionsPatientsPhasePhenotypePhosphotransferasesPhysical condensationProcessProteinsPublic HealthRNARegulationReportingResearchRoleSeriesShort Tandem RepeatSignal TransductionSocietiesStressStructureTemporal LobeToxic effectTranscriptional RegulationTranslationsUntranslated RNAWorkbasebiological adaptation to stressc9FTD/ALSchromatin remodelingeffective therapyfrontal lobefrontotemporal lobar dementia amyotrophic lateral sclerosisgain of functiongenetic approachgenome wide association studygenome-wideinfancyinsightloss of functionnervous system disorderneurotoxicitynovelnovel strategiesnovel therapeutic interventionsporadic amyotrophic lateral sclerosistheories
项目摘要
Project Summary
Nucleotide repeat elements, including microsatellites or short tandem repeats, are
common in eukaryotic genomes. Expansions of short nucleotide repeats have been linked to
over 50 different types of genetic disorders, primarily neurological and neuromuscular disorders.
Our understanding of how these repeat elements in the human genome cause diseases is still
in its infancy. A hexanucleotide repeat expansion in a noncoding region of the C9orf72 gene has
been linked to the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and
frontotemporal dementia (FTD). ALS is characterized by loss of motor neurons, and the C9orf72
hexanucleotide repeat expansion represents the most common genetic cause of both familial
and sporadic ALS. FTD is characterized by degeneration of the frontal and temporal lobes of the
brain and is the second-most common type of dementia in people older than 65; the C9orf72
hexanucleotide repeat expansion is also the most common genetic cause of FTD. This repeat
expansion is also found to contribute to Alzheimer’s disease and Huntington’s disease. To help
relieve the public health burden associated with these diseases, it is important to understand the
mechanisms underlying their pathogenesis. Multiple hypotheses exist to explain the pathogenic
mechanisms underlying C9orf72-linked ALS/FTD. The goal of the proposed project is to
elucidate novel mechanisms through which the C9orf72 hexanucleotide repeat expansion leads
to molecular defects and neuronal toxicity, focusing on gain-of-function mechanisms. The
specific aims are to identify previously unknown pathogenic cascades initiated by the C9orf72
hexanucleotide repeat expansion. These novel pathogenic cascades include, but are not limited
to, RNA toxicity and non-canonical translation products resulting from the C9orf72
hexanucleotide repeat expansion. We propose a series of fundamental studies that combine
biochemical, molecular, and genetic approaches to shed light on the novel pathways leading to
ALS/FTD pathogenesis and to identify potential intervention strategies. Successful completion
of the project is expected to provide insights into fundamental mechanisms of
neurodegeneration in ALS/FTD that may ultimately lead to novel approaches for treating
ALS/FTD and other relevant neurodegenerative diseases.
项目摘要
核苷酸重复元件,包括微卫星或短串联重复序列,
在真核生物基因组中很常见短核苷酸重复序列的扩增与
超过50种不同类型的遗传疾病,主要是神经和神经肌肉疾病。
我们对人类基因组中这些重复元件如何引起疾病的理解仍然是
在它的幼年期。C9 orf 72基因非编码区的六核苷酸重复扩增,
与神经退行性疾病肌萎缩侧索硬化症(ALS)有关,
额颞叶痴呆(FTD)。ALS的特征在于运动神经元的损失,并且C9 orf 72
六核苷酸重复序列扩增代表了两种家族性疾病最常见的遗传原因。
和偶发性肌萎缩性侧索硬化症FTD的特征是额叶和颞叶变性,
大脑,是65岁以上人群中第二常见的痴呆症类型; C9 orf 72
六核苷酸重复扩增也是FTD最常见的遗传原因。该重复
还发现这种扩张有助于阿尔茨海默氏病和亨廷顿氏病。帮助
为了减轻与这些疾病相关的公共卫生负担,了解
其发病机制。存在多种假设来解释致病性
C9 orf 72相关ALS/FTD的潜在机制。拟议项目的目标是
阐明C9 orf 72六核苷酸重复扩增导致
分子缺陷和神经毒性,重点是获得功能的机制。的
具体的目的是确定以前未知的致病级联启动的C9 orf 72
六核苷酸重复扩增。这些新的致病级联反应包括但不限于
RNA毒性和C9 orf 72产生的非经典翻译产物
六核苷酸重复扩增。我们提出了一系列的基础研究,联合收割机
生物化学、分子和遗传学方法来阐明导致
ALS/FTD发病机制,并确定潜在的干预策略。成功完成
预计该项目将提供深入了解基本机制,
ALS/FTD中的神经变性,最终可能导致治疗ALS/FTD的新方法。
ALS/FTD和其他相关神经退行性疾病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jiou Wang的其他文献
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{{ truncateString('Jiou Wang', 18)}}的其他基金
Molecular Basis of Pathogenic Cascades in ALS/FTD Initiated from C9orf72 Hexanucleotide Repeat Expansion
C9orf72 六核苷酸重复扩增引发 ALS/FTD 致病级联的分子基础
- 批准号:
10512236 - 财政年份:2022
- 资助金额:
$ 62.1万 - 项目类别:
Mechanisms of RNA and Protein Dysregulations in ALS/FTD Associated with FUS and Ubiquilin 2
与 FUS 和泛素 2 相关的 ALS/FTD 中 RNA 和蛋白质失调的机制
- 批准号:
10530653 - 财政年份:2019
- 资助金额:
$ 62.1万 - 项目类别:
Mechanisms of RNA and Protein Dysregulations in ALS/FTD Associated with FUS and Ubiquilin 2
与 FUS 和泛素 2 相关的 ALS/FTD 中 RNA 和蛋白质失调的机制
- 批准号:
10401555 - 财政年份:2019
- 资助金额:
$ 62.1万 - 项目类别:
Mechanisms of RNA and Protein Dysregulations in ALS/FTD Associated with FUS and Ubiquilin 2
与 FUS 和泛素 2 相关的 ALS/FTD 中 RNA 和蛋白质失调的机制
- 批准号:
10318610 - 财政年份:2019
- 资助金额:
$ 62.1万 - 项目类别:
Investigating the role of C9orf72 in autophagic and metabolic dysregulation in ALS/FTD
研究 C9orf72 在 ALS/FTD 自噬和代谢失调中的作用
- 批准号:
10400837 - 财政年份:2015
- 资助金额:
$ 62.1万 - 项目类别:
Investigating the role of C9orf72 in autophagic and metabolic dysregulation in ALS/FTD
研究 C9orf72 在 ALS/FTD 自噬和代谢失调中的作用
- 批准号:
10606605 - 财政年份:2015
- 资助金额:
$ 62.1万 - 项目类别:
Investigating the role of C9orf72 in autophagic and metabolic dysregulation in ALS/FTD
研究 C9orf72 在 ALS/FTD 自噬和代谢失调中的作用
- 批准号:
10133157 - 财政年份:2015
- 资助金额:
$ 62.1万 - 项目类别:
Investigating disease Mechanisms in C9orf72-linked ALS/FTD
研究 C9orf72 相关 ALS/FTD 的疾病机制
- 批准号:
9066822 - 财政年份:2015
- 资助金额:
$ 62.1万 - 项目类别:
Investigating the role of C9orf72 in autophagic and metabolic dysregulation in ALS/FTD
研究 C9orf72 在 ALS/FTD 自噬和代谢失调中的作用
- 批准号:
9904831 - 财政年份:2015
- 资助金额:
$ 62.1万 - 项目类别:
Neurodegeneration and Proteotoxicity Dissected in C. elegans and Mammals
线虫和哺乳动物的神经变性和蛋白质毒性剖析
- 批准号:
9281039 - 财政年份:2011
- 资助金额:
$ 62.1万 - 项目类别: