Tools for regulated expression control of miR-218

用于调控 miR-218 表达控制的工具

基本信息

  • 批准号:
    10196829
  • 负责人:
  • 金额:
    $ 19.24万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-05-15 至 2022-11-30
  • 项目状态:
    已结题

项目摘要

MiR-218 is a motor neuron-specific microRNA conserved across vertebrate evolution that is expressed by both fetal and adult lower motor neurons in humans and mice. There are two alleles of miR-218 in humans and mice, and null alleles of both miR-218-1 and miR-218-2 have been generated. It was found that embryos lacking both alleles of miR-218 develop normally with proper motor neuron numbers, however during the final week of embryonic development their motor neurons degenerate with a pathophysiology that mimics spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). Although motor degeneration in ALS occurs in adults rather than at fetal stages as observed in miR-218 mutant mice, several findings provide further indirect support for a connection between ALS and miR-218: (1) Gene expression studies to identify microRNAs dysregulated in sporadic and familial ALS repeatedly detect downregulation of miR-218. (2) A recent analysis of ALS patients found a cohort with mutations in miR-218, suggesting insufficient miR-218 levels or activity may be a risk factor for the disease. (3) Many ALS-linked genes affect RNA metabolism and microRNA processing complexes, including TDP43, FUS and C9orf72, suggesting a plausible mechanism for miR-218 downregulation in ALS. (4) In preliminary studies a floxed-mutation of miR-218 was generated and it was found that deletion in adults leads to neuromuscular pathology. These observations suggest several obvious research possibilities, including tests to: (1) determine whether genetically-lowering miR-218 accelerates ALS-pathology in animal models and (2) whether ectopic miR-218 can reprogram the normal genetic circuits in motor neurons and attenuate ALS degeneration. The goal of this grant is to generate and provide miR-218 reagents to the ALS research community to accelerate the investigation of this promising new candidate for ALS-therapy. In Aim 1, the concentration levels of miR-218 will be defined in an allelic series of mouse lines. It is anticipated that these lines can be used by others to cross to their ALS-models systematically to raise the lower miR-218 levels in vivo. In Aim 2 mouse embryonic stem cell lines (mESC) will be derived from our allelic series of miR-218 lines which is anticipated to have value in culture assays since motor neurons with different miR-218 levels can easily and efficiently be generated from mES lines for investigating the cellular/molecular features of ALS in vitro. The reagents generated in this grant will be made widely available to researchers by depositing our mouse strains in the Jackson Laboratories repository and by maintaining a dedicated stock of mES cell lines for distribution. non- overlapping complementary R21 grant has also been submitted to characterize the genetic networks regulated by miR-218, in order to define mechanistically the motor neuron synaptic and survival modules regulated by this microRNA.
MiR-218是一种在脊椎动物进化过程中保守的运动神经元特异性microRNA,由两者表达

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(0)

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SAMUEL L. PFAFF其他文献

SAMUEL L. PFAFF的其他文献

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{{ truncateString('SAMUEL L. PFAFF', 18)}}的其他基金

Characterization of spinal circuits underlying motor synergy function
运动协同功能背后的脊髓回路的表征
  • 批准号:
    10281130
  • 财政年份:
    2021
  • 资助金额:
    $ 19.24万
  • 项目类别:
Characterization of spinal circuits underlying motor synergy function
运动协同功能背后的脊髓回路的表征
  • 批准号:
    10687832
  • 财政年份:
    2021
  • 资助金额:
    $ 19.24万
  • 项目类别:
Characterization of spinal circuits underlying motor synergy function
运动协同功能背后的脊髓回路的表征
  • 批准号:
    10478289
  • 财政年份:
    2021
  • 资助金额:
    $ 19.24万
  • 项目类别:
MiR-218 regulatory networks in adult mice and its relationship to ALS
成年小鼠的 MiR-218 调控网络及其与 ALS 的关系
  • 批准号:
    10196817
  • 财政年份:
    2021
  • 资助金额:
    $ 19.24万
  • 项目类别:
RP3: Cell Phenotyping: Intrinsic physiology and genetic characteristics
RP3:细胞表型:内在生理学和遗传特征
  • 批准号:
    10011920
  • 财政年份:
    2019
  • 资助金额:
    $ 19.24万
  • 项目类别:
RP3: Cell Phenotyping: Intrinsic physiology and genetic characteristics
RP3:细胞表型:内在生理学和遗传特征
  • 批准号:
    10226043
  • 财政年份:
    2019
  • 资助金额:
    $ 19.24万
  • 项目类别:
RP3: Cell Phenotyping: Intrinsic physiology and genetic characteristics
RP3:细胞表型:内在生理学和遗传特征
  • 批准号:
    10696198
  • 财政年份:
    2019
  • 资助金额:
    $ 19.24万
  • 项目类别:
RP3: Cell Phenotyping: Intrinsic physiology and genetic characteristics
RP3:细胞表型:内在生理学和遗传特征
  • 批准号:
    9815389
  • 财政年份:
    2019
  • 资助金额:
    $ 19.24万
  • 项目类别:
Novel mechanistic study of CMT2D neuropathy
CMT2D 神经病的新机制研究
  • 批准号:
    8656827
  • 财政年份:
    2013
  • 资助金额:
    $ 19.24万
  • 项目类别:
Novel mechanistic study of CMT2D neuropathy
CMT2D 神经病的新机制研究
  • 批准号:
    8572006
  • 财政年份:
    2013
  • 资助金额:
    $ 19.24万
  • 项目类别:

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