NAD metabolsim and mitochondrial dysfunction in ALS models

ALS 模型中的 NAD 代谢和线粒体功能障碍

基本信息

  • 批准号:
    9065661
  • 负责人:
  • 金额:
    $ 32.7万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-08-01 至 2020-05-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): The long-term goal of the proposal is to develop new therapeutic strategies using mechanistic insights drawn from understanding astrocyte-motor neuron interaction in amyotrophic lateral sclerosis (ALS). In particular, the primary objective of this proposal is to establish whether increased nicotinamide adenine dinucleotide (NAD) availability ameliorates motor neuron degeneration in ALS models. ALS or Lou Gehrig's disease accounts for about 1 in 500 to 1 in 1,000 adult deaths in the United States and is caused by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. Motor neuron death leads to muscle weakness and paralysis causing death in one to five years from the time of symptoms onset. Most ALS cases are sporadic (SALS) and exposure to yet unidentified environmental toxicants might be responsible for SALS. About 5-10% of the cases are inherited (familial ALS, FALS) but FALS and SALS are phenotypically indistinguishable, and a significant share of our understanding come from the study of rodent models over-expressing ALS-linked mutant human superoxide dismutase 1 (hSOD1). Primary astrocytes isolated from mutant hSOD1 over-expressing mice induce motor neuron death in co-culture, and it has been demonstrated that astrocytes differentiated from spinal cord autopsy-derived neuronal progenitor cells from FALS and SALS patients are also toxic for motor neurons in co-culture. Sirtuins are a family of enzymes capable of catalyzing NAD-dependent deacylation and mono(ADPribosyl)ation reactions. Remarkably, NAD- dependent sirtuin-mediated deacetylation has been shown to modulate all major mitochondrial processes. Since mitochondrial dysfunction has been linked to ALS and the toxicity of ALS-astrocytes, we seek to better define the role of NAD-dependent signaling in motor neuron degeneration and determine if the modulation of NAD levels may be a potential therapeutic strategy for ALS. Our ongoing experiments demonstrate that increasing NAD content in ALS-astrocytes reverts its toxicity towards co-cultured motor neurons, while NAD synthesis and NAD-dependent signaling may be compromised in mutant hSOD1 mice. Thus, the specific aims of the proposal are: Aim 1-To determine the role of NAD content in the toxicity of astrocytes expressing ALS- linked mutant hSOD1s toward co-cultured motor neurons. Aim 2-To evaluate the effect of transgenic models with altered NAD synthesis and degradation on the onset and progression of the disease in ALS mouse models. Aim 3-To evaluate the effect of treatment with a key NAD precursor on the onset and progression of the disease in ALS mouse models. The outcome of the proposal will contribute to the current understanding of NAD metabolism and mitochondrial dysfunction in neurodegeneration. More important, since we have shown that therapeutic targets identified in our astrocyte-motor neuron co-culture system have a beneficial effect when translated into animal models of ALS, the proposal is likely to provide in vivo proof of the value of modulating NAD metabolism as a therapeutic target in ALS.


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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Marcelo R Vargas其他文献

Modulation of p75NTR‐dependent motor neuron death by a small non‐peptidyl mimetic of the neurotrophin loop 1 domain
神经营养素环 1 结构域的小型非肽基模拟物调节 p75NTR 依赖性运动神经元死亡
  • DOI:
    10.1111/j.1460-9568.2006.05040.x
  • 发表时间:
    2006
  • 期刊:
  • 影响因子:
    3.4
  • 作者:
    Mariana Pehar;P. Cassina;Marcelo R Vargas;Youmei Xie;Joseph S Beckman;S. Massa;F. Longo;L. Barbeito
  • 通讯作者:
    L. Barbeito

Marcelo R Vargas的其他文献

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{{ truncateString('Marcelo R Vargas', 18)}}的其他基金

Role of FABP7 in ALS models
FABP7 在 ALS 模型中的作用
  • 批准号:
    10278460
  • 财政年份:
    2021
  • 资助金额:
    $ 32.7万
  • 项目类别:
Role of FABP7 in ALS models
FABP7 在 ALS 模型中的作用
  • 批准号:
    10415000
  • 财政年份:
    2021
  • 资助金额:
    $ 32.7万
  • 项目类别:
Role of FABP7 in ALS models
FABP7 在 ALS 模型中的作用
  • 批准号:
    10605285
  • 财政年份:
    2021
  • 资助金额:
    $ 32.7万
  • 项目类别:
Circadian Timekeeping, Oxidative Stress and Metabolism in ALS Models
ALS 模型中的昼夜节律、氧化应激和代谢
  • 批准号:
    10086120
  • 财政年份:
    2020
  • 资助金额:
    $ 32.7万
  • 项目类别:
NAD+ metabolism and signaling in ALS models
ALS 模型中的 NAD 代谢和信号传导
  • 批准号:
    10455545
  • 财政年份:
    2020
  • 资助金额:
    $ 32.7万
  • 项目类别:
NAD+ metabolism and signaling in ALS models
ALS 模型中的 NAD 代谢和信号传导
  • 批准号:
    10267190
  • 财政年份:
    2020
  • 资助金额:
    $ 32.7万
  • 项目类别:
NAD+ metabolism and signaling in ALS models
ALS 模型中的 NAD 代谢和信号传导
  • 批准号:
    10670737
  • 财政年份:
    2020
  • 资助金额:
    $ 32.7万
  • 项目类别:
NAD metabolism and mitochondrial dysfunction in ALS models
ALS 模型中的 NAD 代谢和线粒体功能障碍
  • 批准号:
    10084091
  • 财政年份:
    2015
  • 资助金额:
    $ 32.7万
  • 项目类别:
NAD metabolsim and mitochondrial dysfunction in ALS models
ALS 模型中的 NAD 代谢和线粒体功能障碍
  • 批准号:
    9267550
  • 财政年份:
    2015
  • 资助金额:
    $ 32.7万
  • 项目类别:
NAD metabolsim and mitochondrial dysfunction in ALS models
ALS 模型中的 NAD 代谢和线粒体功能障碍
  • 批准号:
    8904927
  • 财政年份:
    2015
  • 资助金额:
    $ 32.7万
  • 项目类别:

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