Neuroinflammation and motor neuron loss in SMA

SMA 中的神经炎症和运动神经元损失

基本信息

  • 批准号:
    10863314
  • 负责人:
  • 金额:
    $ 56.51万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-01 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Spinal muscular atrophy (SMA), a leading genetic cause of infant mortality, is a degenerative disease characterized by loss of motor neurons in the spinal cord, skeletal muscle atrophy, and death. SMA is caused by the disruption or deletion of the survival motor neuron (SMN) gene and a substantial reduction in the associated SMN protein; however, the specific role SMN loss plays in disease pathology is still unclear. Current therapies replace and/or increase SMN levels in patients, and although this strategy is largely successful, it is surprisingly not a cure even when treatment initiates in pre-symptomatic stages. Motor neuron loss is essential for the development of SMA, but the mechanisms underlying motor neuron loss is unknown. Growing evidence from our group and others suggests that astrocytes contribute to the complex SMA phenotype and motor neuron loss. We have found that SMA astrocytes (i) exhibit altered morphology, (ii) lack growth factor production, (iii) have aberrant MAPK signaling, (iv) have increased nuclear localization of NFκB, (v) show aberrant upregulation of GATA6 expression, (vi) exhibit increased cytokine expression, (vii) differentially express and produce microRNAs, and (viii) directly induce motor neuron loss in mouse and human iPSC models. SMA patient postmortem tissues also demonstrate astrogliosis and increased cytokine expression providing important confirmation of the experimental results. SMA microglia also show altered activation states, proteolytic activity and phagocytosis, and our recent data demonstrate that astrocytes further induce microglial malfunction. Notably, astrocyte abnormalities occur very early in the disease process, prior to overt motor neuron loss and microglial malfunction leading us to conceptually advance the premise that astrocytes drive the disease- modifying neuroinflammatory cascade in SMA. Based on our extensive published and preliminary data, we hypothesize that a GATA6-mediated cytokine cascade underlies astrocyte malfunction and disease pathology via both contact dependent and independent mechanisms. Here we will leverage our extensive expertise in SMA, iPSC disease modeling, gene therapy, and surface proteomics to elucidate the molecular mechanisms causing astrocyte dysfunction and the downstream impacts on microglial function and motor neuron survival. The collaborative team is highly experienced in all aspects of the proposed experiments and is poised to make impacts on our foundational understanding of human glial-neuron interactions in health and disease. The long-term objective is to identify novel non-SMN therapeutic targets to supplement currently approved therapies, and the proposed experiments make great strides toward achieving that goal.
项目总结

项目成果

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Barrington G Burnett其他文献

Barrington G Burnett的其他文献

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{{ truncateString('Barrington G Burnett', 18)}}的其他基金

Calcium Dysregulation and Cell Function in Spinal Muscular Atrophy
脊髓性肌萎缩症中的钙失调和细胞功能
  • 批准号:
    10623012
  • 财政年份:
    2022
  • 资助金额:
    $ 56.51万
  • 项目类别:
Calcium Dysregulation and Cell Function in Spinal Muscular Atrophy
脊髓性肌萎缩症中的钙失调和细胞功能
  • 批准号:
    10331028
  • 财政年份:
    2021
  • 资助金额:
    $ 56.51万
  • 项目类别:
Calcium Dysregulation and Cell Function in Spinal Muscular Atrophy
脊髓性肌萎缩症中的钙失调和细胞功能
  • 批准号:
    10759935
  • 财政年份:
    2021
  • 资助金额:
    $ 56.51万
  • 项目类别:
Calcium Dysregulation and Cell Function in Spinal Muscular Atrophy
脊髓性肌萎缩症中的钙失调和细胞功能
  • 批准号:
    10543097
  • 财政年份:
    2021
  • 资助金额:
    $ 56.51万
  • 项目类别:
Targeting the Ubiquitin Proteasome System to Treat Spinal Muscular Atrophy
靶向泛素蛋白酶体系统治疗脊髓性肌萎缩症
  • 批准号:
    9106740
  • 财政年份:
    2016
  • 资助金额:
    $ 56.51万
  • 项目类别:
Targeting the Ubiquitin Proteasome System to Treat Spinal Muscular Atrophy
靶向泛素蛋白酶体系统治疗脊髓性肌萎缩症
  • 批准号:
    9250820
  • 财政年份:
    2016
  • 资助金额:
    $ 56.51万
  • 项目类别:

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