Understanding and Manipulating the Degradation of the C9orf72 Repeat Expansion RNA
了解和操纵 C9orf72 重复扩增 RNA 的降解
基本信息
- 批准号:10578669
- 负责人:
- 金额:$ 4.03万
- 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:2022-03-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAdenosineAffectC9ORF72Cell NucleusCellsCytoplasmDegradation PathwayDevelopmentDipeptidesDiseaseEnzymesEukaryotic CellExcisionExonucleaseFellowshipFluorescent in Situ HybridizationFutureGenesGeneticGoalsInheritedIntronsKnowledgeLearningMethodsModificationMutateMutationNeurodegenerative DisordersNeuronsNuclearOligonucleotidesPathogenesisPathologicPatientsPersonsPhosphodiesterase IProcessProteinsRNARNA DecayRNA DegradationRNA SequencesRNA StabilityRNA-Binding ProteinsResistanceStructureTailTestingTherapeuticTherapeutic InterventionToxic effectTranslatingTranslationsUbiquitinationUntranslated RNAUridineWorkburden of illnessc9FTD/ALSdesignexosomefrontotemporal lobar dementia amyotrophic lateral sclerosismRNA Precursorneurotoxicitynovel therapeutic interventionposttranscriptionalpreventrecruitresponse
项目摘要
PROJECT SUMMARY/ABSTRACT
Understanding and Manipulating the Degradation of the C9orf72 Repeat Expansion RNA
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive, fatal
neurodegenerative diseases. The most common cause of hereditary ALS and FTD is an expansion of the G4C2
sequence in an intron of the C9orf72 gene (c9ALS/FTD). A hallmark pathologic feature of c9ALS/FTD is the
presence of repeat expansion RNA foci in neuronal nuclei, which is unusual because introns are usually
degraded too rapidly to be easily detected. The accumulating G4C2 repeat expansion RNA is thought to
contribute to c9ALS/FTD disease development in two ways: it can sequester RNA-binding proteins and disrupt
their function, and it can be exported into the cytoplasm for translation into toxic dipeptide repeat proteins.
The persistence of the repeat expansion RNA suggests that it forms a stable RNA structure that resists the
normal intron degradation machinery. However, eukaryotic cells contain specific mechanisms for the
degradation of RNAs with strong secondary structures. Such RNAs are post-transcriptionally modified with 3'
oligo-uridine or oligo-adenosine tails that then recruit processive 3' to 5' exonucleases to degrade the RNA. I
hypothesize that the C9orf72 repeat RNA is a poor substrate for normal intronic degradation pathways and that
3’ end tailing determines its rate of decay. To test this, the goal of this proposal is two-fold: I will determine the
composition of the repeat expansion RNA that accumulates into nuclear foci to learn where intronic
degradation is stalling (Aim 1), and I will examine the changes to the sequence and levels of the
G4C2 repeat expansion RNA in response to perturbations to 3’ end tailing, tail removal, and RNA degradation
(Aim 2). Taken together, these studies present an exciting opportunity to discover the mechanisms that
promote degradation of the toxic repeat expansion RNA and, potentially, the ability to accelerate its decay to
reduce toxicity. If successful, the knowledge gained from this work could guide future therapeutic design for
c9ALS/FTD.
项目总结/摘要
理解和操纵C9 orf 72重复扩增RNA的降解
肌萎缩侧索硬化症(ALS)和额颞叶痴呆症(FTD)是进行性的,致命的
神经退行性疾病遗传性ALS和FTD最常见的原因是G4 C2的扩增。
C9 orf 72基因(c9 ALS/FTD)内含子中的序列。c9 ALS/FTD的标志性病理特征是
在神经元核中存在重复扩增RNA灶,这是不寻常的,因为内含子通常
降解得太快而不容易被检测到。积累的G4 C2重复扩增RNA被认为是
通过两种方式促进c9 ALS/FTD疾病的发展:它可以隔离RNA结合蛋白,
它们的功能,它可以输出到细胞质翻译成有毒的二肽重复蛋白。
重复扩增RNA的持续存在表明它形成了一种稳定的RNA结构,
正常的内含子降解机制。然而,真核细胞含有特定的机制,
降解具有强二级结构的RNA。这种RNA是用3'端RNA进行转录后修饰的。
寡聚尿苷或寡聚腺苷尾,然后募集进行性3'至5'核酸外切酶以降解RNA。我
假设C9 orf 72重复RNA是正常内含子降解途径的不良底物,
3'末端拖尾决定其衰变速率。为了验证这一点,本提案的目标是双重的:我将确定
重复扩增RNA的组成,积累到核灶,以了解内含子
降级正在停滞(目标1),我将检查对
G4 C2重复扩增RNA响应于3'末端加尾、去尾和RNA降解的扰动
(Aim 2)。总之,这些研究提供了一个令人兴奋的机会来发现
促进毒性重复扩增RNA的降解,并潜在地加速其衰变,
降低毒性。如果成功,从这项工作中获得的知识可以指导未来的治疗设计,
c9ALS/FTD。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Soraya I Shehata其他文献
Soraya I Shehata的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Soraya I Shehata', 18)}}的其他基金
Understanding and Manipulating the Degradation of the C9orf72 Repeat Expansion RNA
了解和操纵 C9orf72 重复扩增 RNA 的降解
- 批准号:
10387697 - 财政年份:2022
- 资助金额:
$ 4.03万 - 项目类别:
相似国自然基金
基于ADK/Adenosine调控DNA甲基化探讨“利湿化瘀通络”法对2型糖尿病肾病足细胞裂孔膜损伤的干预机制研究
- 批准号:82074359
- 批准年份:2020
- 资助金额:55 万元
- 项目类别:面上项目
细胞外腺苷(Adenosine)作为干细胞旁分泌因子的生物学鉴定和功能分析
- 批准号:81570244
- 批准年份:2015
- 资助金额:57.0 万元
- 项目类别:面上项目
Adenosine诱导A1/A2AR稳态失衡启动慢性低灌注白质炎性损伤及其机制
- 批准号:81171113
- 批准年份:2011
- 资助金额:55.0 万元
- 项目类别:面上项目
相似海外基金
Targeting the A2B Adenosine Receptor for Immunoprevention of Pancreatic Cancer
靶向 A2B 腺苷受体用于胰腺癌的免疫预防
- 批准号:
10929664 - 财政年份:2023
- 资助金额:
$ 4.03万 - 项目类别:
Exploring the role of adenosine A2A receptors in Schizophrenia using opto-pharmacologically controlled allosteric modulation.
利用光药理学控制的变构调节探索腺苷 A2A 受体在精神分裂症中的作用。
- 批准号:
23K14685 - 财政年份:2023
- 资助金额:
$ 4.03万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
The Role of Adenosine Kinase in Mixed Diastolic Heart Failure and Alzheimer Disease
腺苷激酶在混合性舒张性心力衰竭和阿尔茨海默病中的作用
- 批准号:
10679989 - 财政年份:2023
- 资助金额:
$ 4.03万 - 项目类别:
Allostery-driven G protein selectivity in the adenosine A1 receptor
腺苷 A1 受体中变构驱动的 G 蛋白选择性
- 批准号:
BB/W016974/1 - 财政年份:2023
- 资助金额:
$ 4.03万 - 项目类别:
Research Grant
Investigation of new test methods for adenosine-sensitive atrioventricular block
腺苷敏感型房室传导阻滞新检测方法的探讨
- 批准号:
23K07566 - 财政年份:2023
- 资助金额:
$ 4.03万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Probing the role of adenosine pathway in SIV pathogenesis
探讨腺苷途径在 SIV 发病机制中的作用
- 批准号:
10760676 - 财政年份:2023
- 资助金额:
$ 4.03万 - 项目类别:
The role of A1 adenosine receptor signaling in the decline of S. pneumoniae killing by neutrophils in vaccinated aged hosts
A1 腺苷受体信号传导在疫苗接种老年宿主中中性粒细胞杀伤肺炎链球菌下降中的作用
- 批准号:
10605737 - 财政年份:2023
- 资助金额:
$ 4.03万 - 项目类别:
Adenosine triphosphate as a master variable for biomass in the oceanographic context
三磷酸腺苷作为海洋学背景下生物量的主变量
- 批准号:
2319114 - 财政年份:2023
- 资助金额:
$ 4.03万 - 项目类别:
Standard Grant
The Biology of Microglia: Adenosine A3 Receptor Suppression
小胶质细胞的生物学:腺苷 A3 受体抑制
- 批准号:
RGPIN-2019-06289 - 财政年份:2022
- 资助金额:
$ 4.03万 - 项目类别:
Discovery Grants Program - Individual
Postnatal development of adenosine kinase in the brainstem network that controls breathing
控制呼吸的脑干网络中腺苷激酶的出生后发育
- 批准号:
573323-2022 - 财政年份:2022
- 资助金额:
$ 4.03万 - 项目类别:
University Undergraduate Student Research Awards