A new DMD model with a humanized glycome

具有人源化糖组的新 DMD 模型

基本信息

项目摘要

DESCRIPTION (provided by applicant): In this grant, we propose to define the role of an important human-specific change in glycosylation, the loss of N-glycolylneuraminic acid (Neu5Gc), in Duchenne muscular dystrophy (DMD) and in Limb Girdle Muscular Dystrophy 2D. Neu5Gc is a form of sialic acid that is absent in all humans due to an inactivating mutation in the human CMAH gene. By contrast, Neu5Gc is an abundant form of sialic acid in heart and skeletal muscles in almost all other mammals besides humans, including the great apes. To assess the role of human CMAH in DMD, we have created Cmah-/-mdx mice, in effect humanizing this aspect of mouse glycosylation. The mdx mouse has been studied for several decades as a model for DMD, a relatively common and ultimately fatal X- linked neuromuscular disorder. Despite mimicking loss of dystrophin, the gene defective in DMD, in almost all muscle cells, mdx mice do not show the mouse equivalent of a pediatric presentation of disease. Children with DMD show loss of ambulation, usually by 12 years of age, followed by respiratory and/or cardiac failure and death usually in the third decade of life. mdx mice, by contrast, show little change in these same features until near the end of their normal lifespan, which is typically reduced by only 1-2 months relative to wild type animals. Cmah-/-mdx mice, by contrast to mdx animals, show an 88% deficit in diaphragm muscle strength and a 66% deficit in cardiac trabecular muscle strength, compared to wild type, by 8 months of age, with half of animals dying by 11 months. Such mice also show significantly impaired ambulation relative to mdx. The early and robust presentation of these phenotypes, which are the primary drivers of DMD morbidity and mortality, in a small animal model that carries a genetically appropriate human-like change in the mouse genome will be a great asset to translational research to identify therapies for DMD and other human diseases. In Aim 1 of this proposal, we will investigate both the loss of function aspects to Neu5Gc deficiency as well as gain of function immune aspects as they relate to disease severity in Cmah-/-mdx mice. In Aim 2, we will devise therapies to offset the increased disease severity resulting from deletion of Cmah that could be translated into therapies for muscular dystrophy patients. In Aim 3, we will study the role of Cmah in a second mouse model of muscular dystrophy, the Sgca-/- model of Limb Girdle Muscular Dystrophy 2D. These experiments will investigate the cause of increased disease severity resulting from Cmah deficiency, assess the generality of Cmah deficiency in altering disease, and develop therapies to offset the loss of human CMAH that could ameliorate muscular dystrophy in DMD and LGMD2D patients.
描述(由申请人提供):在这项拨款中,我们建议定义在杜氏肌营养不良症(DMD)和肢带肌营养不良症2D中,糖基化、n-糖基化神经氨酸(Neu5Gc)缺失中重要的人类特异性变化的作用。Neu5Gc是一种唾液酸,由于人类CMAH基因的失活突变,在所有人类中都不存在。相比之下,除了人类,包括类人猿在内的几乎所有其他哺乳动物的心脏和骨骼肌中都含有大量的Neu5Gc唾液酸。为了评估人类CMAH在DMD中的作用,我们创造了CMAH -/-mdx小鼠,有效地将小鼠糖基化的这一方面人源化。mdx小鼠作为DMD模型已经被研究了几十年,DMD是一种相对常见且最终致命的与X染色体相关的神经肌肉疾病。尽管mdx小鼠几乎在所有肌肉细胞中都模仿了肌营养不良蛋白(DMD的基因缺陷)的缺失,但mdx小鼠并没有表现出与儿科疾病相同的小鼠症状。患有DMD的儿童通常在12岁时丧失行走能力,随后出现呼吸和/或心脏衰竭,通常在生命的第三个十年死亡。相比之下,MDX小鼠在这些相同的特征上几乎没有变化,直到它们的正常寿命接近尾声,相对于野生型动物,这通常只减少了1-2个月。与mdx小鼠相比,Cmah-/-mdx小鼠在8个月大时膈肌力量下降88%,心脏小梁肌肉力量下降66%,其中一半的动物在11个月大时死亡。与mdx相比,这些小鼠的行走能力也明显受损。这些表型是DMD发病率和死亡率的主要驱动因素,在小鼠基因组中携带遗传上适当的人类样变化的小动物模型中,这些表型的早期和强大的表现将是确定DMD和其他人类疾病治疗方法的转化研究的重要资产。在本提案的目的1中,我们将研究Cmah-/-mdx小鼠中Neu5Gc缺陷的功能丧失以及功能免疫方面的获得,因为它们与疾病严重程度有关。在Aim 2中,我们将设计治疗方法来抵消Cmah缺失导致的疾病严重程度增加,这可以转化为肌肉萎缩症患者的治疗方法。在Aim 3中,我们将研究Cmah在第二种肌肉萎缩症小鼠模型中的作用,即肢体带状肌肉萎缩症2D的Sgca-/-模型。这些实验将研究Cmah缺乏导致疾病严重程度增加的原因,评估Cmah缺乏在改变疾病中的普遍性,并开发可以改善DMD和LGMD2D患者肌肉萎缩症的治疗方法来抵消人类Cmah的损失。

项目成果

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PAUL Taylor MARTIN其他文献

PAUL Taylor MARTIN的其他文献

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{{ truncateString('PAUL Taylor MARTIN', 18)}}的其他基金

Micro-laminin Gene Therapy for MDC1A
MDC1A 的微层粘连蛋白基因治疗
  • 批准号:
    10393047
  • 财政年份:
    2021
  • 资助金额:
    $ 51.14万
  • 项目类别:
Micro-laminin Gene Therapy for MDC1A
MDC1A 的微层粘连蛋白基因治疗
  • 批准号:
    10198254
  • 财政年份:
    2021
  • 资助金额:
    $ 51.14万
  • 项目类别:
Project 1: Preclinical development of surrogate gene therapy using GALGT2
项目1:利用GALGT2进行替代基因治疗的临床前开发
  • 批准号:
    10017023
  • 财政年份:
    2016
  • 资助金额:
    $ 51.14万
  • 项目类别:
Development of a novel HIBM2 mouse model and therapy
新型 HIBM2 小鼠模型和疗法的开发
  • 批准号:
    8808258
  • 财政年份:
    2015
  • 资助金额:
    $ 51.14万
  • 项目类别:
A myoutube-specific deletion model for sarcopenia
肌肉减少症的肌管特异性缺失模型
  • 批准号:
    8302840
  • 财政年份:
    2012
  • 资助金额:
    $ 51.14万
  • 项目类别:
A new DMD model with a humanized glycome
具有人源化糖组的新 DMD 模型
  • 批准号:
    9071078
  • 财政年份:
    2012
  • 资助金额:
    $ 51.14万
  • 项目类别:
A myoutube-specific deletion model for sarcopenia
肌肉减少症的肌管特异性缺失模型
  • 批准号:
    8454456
  • 财政年份:
    2012
  • 资助金额:
    $ 51.14万
  • 项目类别:
A new DMD model with a humanized glycome
具有人源化糖组的新 DMD 模型
  • 批准号:
    8449165
  • 财政年份:
    2012
  • 资助金额:
    $ 51.14万
  • 项目类别:
A new DMD model with a humanized glycome
具有人源化糖组的新 DMD 模型
  • 批准号:
    9057366
  • 财政年份:
    2012
  • 资助金额:
    $ 51.14万
  • 项目类别:
A new DMD model with a humanized glycome
具有人源化糖组的新 DMD 模型
  • 批准号:
    8825418
  • 财政年份:
    2012
  • 资助金额:
    $ 51.14万
  • 项目类别:

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