RNA-Targeted Dysregulation of Survival Factors in ALS: HuR to the Rescue

ALS 中生存因子的 RNA 靶向失调:HuR 来拯救

基本信息

  • 批准号:
    8774160
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-01-01 至 2015-12-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a degenerative disease of motor neurons that inexorably leads to progressive weakness and death. The incidence of ALS is significantly increased among veterans of foreign wars, and thus it has a major impact on veteran health care. Sadly, the pathophysiology of this disease remains largely a mystery, and there are no effective treatments. In recent work from our laboratory, we have identified dysregulation of growth factor mRNA stability and translation as a novel mechanistic direction to understanding the basis for ALS. Mutations of Cu, Zn superoxide dismutase (SOD)1 that are associated with familial ALS gain a high RNA binding affinity for U- and AU-rich elements present in 5' and 3' untranslated regions (UTR) of many critical growth and cytoprotective factors. Through an interaction with cellular RNA binding proteins (RBP), these elements govern stability and translation of the transcript and provide an important pathway for rapid upregulation of survival factors during cellular stress. The RBP, HuR, plays a major positive role in this molecular pathway by binding to these elements. We previously showed that mutant SOD1, through its gain of high RNA binding affinity, disrupts HuR stabilization and translation of vascular endothelial growth factor mRNA, a critical neuroprotective factor for motor neurons. We found that apoptosis and mitochondrial dysfunction in cells expressing mutant SOD1 could be reversed by upregulating HuR. Based on this work, we hypothesize here that upregulation of HuR can rescue motor neuron degeneration induced by mutant SOD1 by reversing aberrant post-transcriptional processing of survival factor mRNAs in motor neurons directly or by enhanced VEGF production of surrounding astrocytes. We have the animal cellular models necessary to test this exciting possibility. This work has the real potential to establish a foundation for developing novel therapeutic approaches to this devastating disease. Specific Aims: 1. To determine whether HuR can rescue the cytotoxic phenotype of mutant SOD1 in motor neurons and astrocytes using in vitro and in vivo mouse models. 2. To determine the molecular impact of transgenic HuR expression in motor neurons and astrocytes with regard to posttranscriptional regulation and production of cytoprotective factors.
描述(由申请人提供):

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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PETER H KING其他文献

PETER H KING的其他文献

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{{ truncateString('PETER H KING', 18)}}的其他基金

Therapeutic benefit of targeting neuroinflammation in spinal cord injury with a novel small molecule inhibitor of the RNA regulator HuR
使用 RNA 调节因子 HuR 的新型小分子抑制剂针对脊髓损伤中的神经炎症的治疗益处
  • 批准号:
    10472150
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Role of Microglial Hur in promoting neuroinflammation and ALS disease progression
小胶质细胞 Hur 在促进神经炎症和 ALS 疾病进展中的作用
  • 批准号:
    9559943
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
Role of Microglial Hur in promoting neuroinflammation and ALS disease progression
小胶质细胞 Hur 在促进神经炎症和 ALS 疾病进展中的作用
  • 批准号:
    10421258
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
Role of Microglial Hur in promoting neuroinflammation and ALS disease progression
小胶质细胞 Hur 在促进神经炎症和 ALS 疾病进展中的作用
  • 批准号:
    10046279
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
Smad Signaling in Skeletal Muscle as a Biomarker of Disease Progression in ALS
骨骼肌中的 Smad 信号转导作为 ALS 疾病进展的生物标志物
  • 批准号:
    9222815
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
HuR and RNA regulation as a Novel Therapeutic Target in Malignant Glioma
HuR 和 RNA 调控作为恶性胶质瘤的新治疗靶点
  • 批准号:
    9257249
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
Molecular Signatures of Amyotrophic Lateral Sclerosis in Skeletal Muscle
骨骼肌肌萎缩侧索硬化症的分子特征
  • 批准号:
    8722055
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
Molecular Signatures of Amyotrophic Lateral Sclerosis in Skeletal Muscle
骨骼肌肌萎缩侧索硬化症的分子特征
  • 批准号:
    8619114
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
RNA-Targeted Dysregulation of Survival Factors in ALS: HuR to the Rescue
ALS 中生存因子的 RNA 靶向失调:HuR 来拯救
  • 批准号:
    8242240
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
RNA-Targeted Dysregulation of Survival Factors in ALS: HuR to the Rescue
ALS 中生存因子的 RNA 靶向失调:HuR 来拯救
  • 批准号:
    8413600
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:

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