The Role of the Terminal Complement Pathway in ALS

终末补体通路在 ALS 中的作用

基本信息

  • 批准号:
    8605944
  • 负责人:
  • 金额:
    $ 18.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-02-01 至 2016-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Amyotrophic Lateral Sclerosis (ALS) is a progressive motor neuron disease that leads to degeneration of motor neurons in the cortex, brainstem and spinal cord resulting in progressive paralysis and ultimately death. The occurrence of ALS is largely sporadic (SALS), however approximately five to ten percent of cases are familial, associated with mutations in one of several genes including Cu,Zn SOD-1, Alsin, Senataxin, TDP-43 and FUS/TLS. There is currently no prophylactic therapy or cure for ALS and the only approved treatment, riluzole, extends survival only a few months and is considered ineffective. Given the lack of effective therapies and the estimated lifetime risk of developing SALS ranging from 1 in 400 to 1 in 1000, the need for disease biomarkers and disease-modifying therapies is critical. Neuroinflammation has received attention as a mechanism that participates in motor neuron loss in ALS, due in large part to the recognition of immune-mediated contributions to other neurodegenerative diseases, including multiple sclerosis, Alzheimer's and Parkinson's disease. The complement system, a major arm of the innate immune system, drives neuroinflammation along with other inflammatory mediators in most, if not all, central nervous system diseases and infections. There is growing evidence that complement contributes to neurodegeneration in ALS. Several studies have found evidence of complement activation and deposition in the spinal cord of ALS patients as well as elevated levels of complement activation fragments in cerebrospinal fluid (CSF) or serum. In addition, rodent models of ALS, have shown changes in complement gene expression and complement deposition in motor neurons and neuromuscular junctions in pre- and symptomatic stages of murine ALS. Nevertheless, the role of complement in the development and progression of ALS remains ill-defined. We have taken a systematic approach to address the role of complement in murine ALS by crossing SOD1G93A transgenic mice with mice deficient in C3 or C5, the two central proteins of the complement system. We observed a time-dependent deposition of C9 in the spinal cords of SOD1G93A mice suggesting that the membrane attack complex contributes to neurodegeneration in ALS. Furthermore, we found that female C5+/- x SOD1G93A mice survived significantly longer than the respective genders in SOD1G93A mice, an observation that correlates with the reduced C5 levels in female mice. We hypothesize that C5 plays a central role in the development and progression of ALS and will address this hypothesis by comparing the clinical and histological ALS phenotypes of both genders of mice that are SOD1G93A tg and deficient in C3, C5, C5aR or C9 to SOD1G93A mice. These studies will provide new information regarding the role of complement in ALS and potentially new therapeutic directions.
描述(由申请人提供):肌萎缩性侧索硬化症(ALS)是一种进行性运动神经元疾病,可导致皮质、脑干和脊髓中的运动神经元变性,导致进行性瘫痪并最终死亡。ALS的发生在很大程度上是散发性的(SALS),但是大约5%到10%的病例是家族性的,与几个基因之一的突变有关,包括Cu,Zn SOD-1,Alsin,Senataxin,TDP-43和FUS/TLS。目前还没有ALS的预防性治疗或治愈方法,唯一批准的治疗方法利鲁唑只能延长几个月的生存期,并且被认为是无效的。鉴于缺乏有效的治疗方法,估计发生SALS的终生风险范围为1/400至1/1000,因此对疾病生物标志物和疾病修饰疗法的需求至关重要。神经炎症作为参与ALS中运动神经元损失的机制而受到关注,这在很大程度上是由于认识到免疫介导的对其他神经退行性疾病(包括多发性硬化症、阿尔茨海默病和帕金森病)的贡献。补体系统是先天免疫系统的主要分支,在大多数(如果不是全部的话)中枢神经系统疾病和感染中与其他炎症介质一起驱动神经炎症沿着。越来越多的证据表明,补体有助于ALS的神经变性。几项研究已经发现ALS患者脊髓中补体激活和沉积的证据,以及脑脊液(CSF)或血清中补体激活片段水平升高的证据。此外,ALS的啮齿动物模型已经显示出在鼠ALS的症状前和症状阶段中运动神经元和神经肌肉接头中补体基因表达和补体沉积的变化。然而,补体在ALS的发展和进展中的作用仍然不明确。我们已经采取了一种系统的方法来解决补体在小鼠ALS中的作用,通过将SOD 1G 93 A转基因小鼠与补体系统的两种中心蛋白C3或C5缺陷的小鼠杂交。我们观察到C9在SOD 1G 93 A小鼠脊髓中的时间依赖性沉积,表明膜攻击复合物有助于ALS中的神经变性。此外,我们发现雌性C5+/- x SOD 1G 93 A小鼠的存活时间显著长于SOD 1G 93 A小鼠中相应性别的存活时间,这一观察结果与雌性小鼠中C5水平降低相关。我们假设C5在ALS的发展和进展中起着核心作用,并将通过比较SOD 1G 93 A tg和C3、C5、C5 aR或C9缺陷的两种性别小鼠与SOD 1G 93 A小鼠的临床和组织学ALS表型来解决这一假设。这些研究将提供关于补体在ALS中的作用的新信息和潜在的新治疗方向。

项目成果

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Scott R BARNUM其他文献

Scott R BARNUM的其他文献

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{{ truncateString('Scott R BARNUM', 18)}}的其他基金

The Role of the Terminal Complement Pathway in ALS
终末补体通路在 ALS 中的作用
  • 批准号:
    8511495
  • 财政年份:
    2013
  • 资助金额:
    $ 18.13万
  • 项目类别:
Complement-based Therapeutics in Demyelinating Disease
脱髓鞘疾病中基于补体的治疗
  • 批准号:
    8117574
  • 财政年份:
    2010
  • 资助金额:
    $ 18.13万
  • 项目类别:
Complement-based Therapeutics in Demyelinating Disease
脱髓鞘疾病中基于补体的治疗
  • 批准号:
    7990776
  • 财政年份:
    2010
  • 资助金额:
    $ 18.13万
  • 项目类别:
RBC age and potentiation of transfusion related pathology in trauma patients
创伤患者的红细胞年龄和输血相关病理的增强
  • 批准号:
    8298545
  • 财政年份:
    2009
  • 资助金额:
    $ 18.13万
  • 项目类别:
RBC age and potentiation of transfusion related pathology in trauma patients
创伤患者的红细胞年龄和输血相关病理的增强
  • 批准号:
    7935322
  • 财政年份:
    2009
  • 资助金额:
    $ 18.13万
  • 项目类别:
Generation of complement C9 conditional knockout mice and anti-C9 mAbs
补体 C9 条件敲除小鼠和抗 C9 mAb 的生成
  • 批准号:
    7706326
  • 财政年份:
    2009
  • 资助金额:
    $ 18.13万
  • 项目类别:
Generation of complement C9 conditional knockout mice and anti-C9 mAbs
补体 C9 条件敲除小鼠和抗 C9 mAb 的生成
  • 批准号:
    7860430
  • 财政年份:
    2009
  • 资助金额:
    $ 18.13万
  • 项目类别:
RBC age and potentiation of transfusion related pathology in trauma patients
创伤患者的红细胞年龄和输血相关病理的增强
  • 批准号:
    7760753
  • 财政年份:
    2009
  • 资助金额:
    $ 18.13万
  • 项目类别:
RBC age and potentiation of transfusion related pathology in trauma patients
创伤患者的红细胞年龄和输血相关病理的增强
  • 批准号:
    8106270
  • 财政年份:
    2009
  • 资助金额:
    $ 18.13万
  • 项目类别:
Conference on Central Nervous System Inflammation
中枢神经系统炎症会议
  • 批准号:
    6887144
  • 财政年份:
    2005
  • 资助金额:
    $ 18.13万
  • 项目类别:
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