TDP-43 and FUS RNA pathways in motor neuron degeneration

TDP-43 和 FUS RNA 通路在运动神经元变性中的作用

基本信息

  • 批准号:
    8030493
  • 负责人:
  • 金额:
    $ 24万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-09-01 至 2012-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Dysregulation of RNA pathways is emerging as a central feature of degeneration of motor neurons. Amyotrophic lateral sclerosis (ALS) is the most common human motor neuron degenerative disease with a fatal outcome and without a cure. Approximately 20% of ALS patients also develop Frontotemporal Lobar Degeneration (FTLD), characterized by dementia due to neuronal degeneration and often with the presence of ubiquitinated protein aggregates (FTDL-U). Recent studies have shown that mutations of two RNA Binding Proteins (RBPs) known as TDP-43 (or TARDBP) and FUS (or FUS/TLS) cause familial ALS (FALS) and FTLD-U; and protein aggregates containing TDP-43 or TDP-43 carboxy-terminal (C-terminal) fragments are detected in the majority of sporadic ALS cases and in many cases of FTLD-U (FTLD-TDP), further underscoring the paramount importance of RBPs and of RNA dysregulation in neuronal degeneration. The RNA targets and function of TDP43 and FUS in motor neurons are unknown. Furthermore, it is unknown how mutations of TDP-43 and FUS lead to neuronal degeneration. In this application we propose to develop novel experimental systems and strategies to investigate the function of TDP-43 and FUS in RNA pathways and to dissect pathogenetic mechanisms involved in motor neuron degeneration by TDP-43 and FUS patient mutants. In Aim 1, we will establish and characterize embryonic stem cell derived motor neuron culture systems to investigate TDP-43 and FUS. We will characterize the cellular and molecular effects of mutant TDP-43 and FUS in cultured motor neurons and in the motor neurons of ALS patients. In Aim 2, we will identify RNA target for TDP-43 and FUS in human brain and motor neurons and we will investigate whether TDP-43 and FUS patient mutations result in RNA dysregulation in motor neurons. We expect that our studies will lead to the development of novel experimental systems and will provide critical insights in the function of TDP-43 and FUS in motor neurons and the role of patient mutations in neuronal degeneration. We also anticipate that the outcome of this exploratory R21 grant application may provide important insights that will guide further investigations in therapeutic strategies to combat this lethal disease. PUBLIC HEALTH RELEVANCE: In this application we propose to develop novel experimental systems and strategies to investigate how motor neurons degenerate in ALS, a devastating neurodegenerative disease. We anticipate that our studies may provide important insights that will guide further investigations in therapeutic strategies to combat this lethal disease.
描述(由申请人提供):RNA通路的失调正在成为运动神经元退化的一个中心特征。肌萎缩侧索硬化症(ALS)是人类最常见的运动神经元退行性疾病,其结果是致命的,无法治愈。大约20%的ALS患者还会发展为额颞叶变性(FTLD),其特征是神经元变性导致的痴呆,通常伴随泛素化蛋白聚集体(FTDL-U)的存在。最近的研究表明,两种被称为TDP-43(或TARDBP)和FUS(或FUS/TLS)的RNA结合蛋白(RBPs)的突变可导致家族性ALS(FALS)和FTLD-U;在大多数散发性ALS病例和许多FTLD-U(FTLD-TDP)病例中都检测到含有TDP-43或TDP-43羧基末端(C-末端)片段的蛋白质聚集体,进一步强调了RBPs和RNA调控失调在神经元变性中的极端重要性。TDP43和FUS在运动神经元中的RNA靶点和功能尚不清楚。此外,TDP-43和FUS的突变是如何导致神经元退化的还不清楚。在这一应用中,我们建议开发新的实验系统和策略来研究TDP-43和FUS在RNA通路中的功能,并通过TDP-43和FUS患者的突变来剖析涉及运动神经元变性的致病机制。在目标1中,我们将建立和鉴定胚胎干细胞来源的运动神经元培养系统,以研究TDP-43和FUS。我们将研究突变体TDP-43和FUS在培养的运动神经元和ALS患者的运动神经元中的细胞和分子效应。在目标2中,我们将在人脑和运动神经元中识别TDP-43和FUS的RNA靶标,并将研究TDP-43和FUS患者突变是否导致运动神经元RNA失调。我们期望我们的研究将导致新的实验系统的发展,并将为运动神经元中TDP-43和FUS的功能以及患者突变在神经元退化中的作用提供关键的见解。我们还预计,这一探索性的R21拨款申请的结果可能会提供重要的见解,指导进一步的研究,以对抗这种致命的疾病的治疗策略。 公共卫生相关性:在这项申请中,我们建议开发新的实验系统和策略来研究ALS运动神经元是如何退化的,ALS是一种毁灭性的神经退行性疾病。我们预计,我们的研究可能会提供重要的见解,指导进一步研究抗击这种致命疾病的治疗策略。

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 }}

ZISSIMOS MOURELATOS其他文献

ZISSIMOS MOURELATOS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('ZISSIMOS MOURELATOS', 18)}}的其他基金

Ribothrypsis: mechanisms and implications for gene expression regulation
Ribothrypsis:基因表达调控的机制和影响
  • 批准号:
    9763773
  • 财政年份:
    2019
  • 资助金额:
    $ 24万
  • 项目类别:
Ribothrypsis: mechanisms and implications for gene expression regulation
Ribothrypsis:基因表达调控的机制和影响
  • 批准号:
    10413119
  • 财政年份:
    2019
  • 资助金额:
    $ 24万
  • 项目类别:
Ribothrypsis: mechanisms and implications for gene expression regulation
Ribothrypsis:基因表达调控的机制和影响
  • 批准号:
    10017305
  • 财政年份:
    2019
  • 资助金额:
    $ 24万
  • 项目类别:
Ribothrypsis: mechanisms and implications for gene expression regulation
Ribothrypsis:基因表达调控的机制和影响
  • 批准号:
    10201666
  • 财政年份:
    2019
  • 资助金额:
    $ 24万
  • 项目类别:
Deciphering pachytene piRNA function
破译粗线期 piRNA 功能
  • 批准号:
    9902461
  • 财政年份:
    2018
  • 资助金额:
    $ 24万
  • 项目类别:
Deciphering pachytene piRNA function
破译粗线期 piRNA 功能
  • 批准号:
    9750053
  • 财政年份:
    2018
  • 资助金额:
    $ 24万
  • 项目类别:
TDP-43 and FUS RNA pathways in motor neuron degeneration
TDP-43 和 FUS RNA 通路在运动神经元变性中的作用
  • 批准号:
    8129434
  • 财政年份:
    2010
  • 资助金额:
    $ 24万
  • 项目类别:
LASER-CROSSLINKING OF MICRO-RNPS ON THEIR MRNA TARGET
微型 RNPS 与 mRNA 靶标的激光交联
  • 批准号:
    7598460
  • 财政年份:
    2007
  • 资助金额:
    $ 24万
  • 项目类别:
Genetic Control of RNA metabolism: analysis of the SMARD1 helicase
RNA 代谢的遗传控制:SMARD1 解旋酶的分析
  • 批准号:
    7992374
  • 财政年份:
    2007
  • 资助金额:
    $ 24万
  • 项目类别:
Genetic Control of RNA metabolism: analysis of the SMARD1 helicase
RNA 代谢的遗传控制:SMARD1 解旋酶的分析
  • 批准号:
    7537177
  • 财政年份:
    2007
  • 资助金额:
    $ 24万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了