The Molecular Basis of CMD Types Ullrich and Bethlem
Ullrich 和 Bethlem CMD 类型的分子基础
基本信息
- 批准号:7117293
- 负责人:
- 金额:$ 35.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-09-01 至 2010-06-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): The goal of this grant proposal is to elucidate the molecular mechanisms underlying the severe congenital muscular dystrophy type Ullrich (UCMD) and its milder counterpart Bethlem myopathy (BM). UCMD and BM combine features of muscular dystrophies and disorders of connective tissue resulting in significant weakness, progressive contractures, and joint laxity. Collagen VI is a microfibrillar component found in the extracellular matrix of most tissues, often in a pericellula r distribution . Its basic heterotrimeric unit is composed of three alpha chains. Mutations in the collagen VI genes (COL6A1, COL6A2, COL6A3) have been identified in BM and more recently also in UCMD. Althoug h BM usuall y is caused by dominan t mutations and UCMD by recessive mutations, we recently demonstrated dominan t negative mechanisms in UCMD also. The relevant functions of collagen VI are unclear, in various culture systems it has been shown to promote cell adhesion, differentiation , proliferation , and survival , whereas in a mouse model of Col6al inactivatio n there was evidence for increased apoptosis in the muscle. We hypothesize that fibroblasts are the primary cell type involved in UCMD and BM causing disease both in muscle (weakness) and in tendon (laxity and contractures) by producing an abnormal extracellular matrix (ECM). We further hypothesize that a specific disturbance of the interface between muscle and its extracellular matrix (ECM) leads to muscle apoptosis and weakness. In this project we will comprehensively characterize patients with UCMD and BM to define their clinical, morphological, and biochemical phenotypes and correlate these with the collagen VI genotypes. This will enable us to delineate the entire phenotypical, biochemical, and genetic spectrum of UCMD/BM. We wil l next determine changes in ECM gene expression as well as apoptosis in dermal fibroblasts cultures from the characterized patients with mutations in the collagen VI genes. Defining changes in ECM composition and fibroblast viability will allow us to understand the basis of the congenital and progressive contractures, the joint laxity, and to predict the nature of the abnormal ECM deposited in muscle. To study the molecular basis of the muscle weakness we are developing a novel co-culture system in which various patient derived fibroblast cultures supply an ECM for normal muscle cells. This system will be used to examine the effects of normal and mutant collagen VI matrices on the myotubes in culture. It will allow us to define the pathways that lead to muscle dysfunction and muscle cell death. Ultimately, we hope to understand the influence of ECM on the development of muscular dystrophy. Knowledge about these pathways is a prerequisite for developing effective treatment strategies in this new and important group of muscle disorders.
描述(由申请人提供):本资助提案的目标是阐明严重先天性肌营养不良型乌尔里希(UCMD)及其轻度对应的Bethlem肌病(BM)的分子机制。UCMD和BM结合了肌营养不良和结缔组织疾病的联合收割机特征,导致显著虚弱、进行性挛缩和关节松弛。胶原VI是在大多数组织的细胞外基质中发现的微纤维组分,通常以细胞周分布。它的基本异源三聚体单元由三条α链组成。胶原VI基因(COL 6A 1、COL 6A 2、COL 6A 3)的突变已在BM中发现,最近也在UCMD中发现。虽然BM通常是由显性突变引起,UCMD是由隐性突变引起,但我们最近发现UCMD也存在显性负性机制。胶原VI的相关功能尚不清楚,在各种培养系统中,已显示其促进细胞粘附、分化、增殖和存活,而在Col 6al失活的小鼠模型中,有证据表明肌肉中的细胞凋亡增加。我们假设成纤维细胞是参与UCMD和BM的主要细胞类型,通过产生异常细胞外基质(ECM)引起肌肉(无力)和肌腱(松弛和挛缩)疾病。我们进一步假设,肌肉和其细胞外基质(ECM)之间的界面的特定干扰导致肌肉细胞凋亡和虚弱。在本项目中,我们将全面描述UCMD和BM患者的特征,以确定其临床、形态学和生化表型,并将其与VI型胶原基因型相关联。这将使我们能够描绘整个UCMD/BM的表型,生化和遗传谱。我们接下来将确定来自具有胶原VI基因突变的特征患者的真皮成纤维细胞培养物中ECM基因表达以及细胞凋亡的变化。定义ECM组成和成纤维细胞活力的变化将使我们能够理解先天性和进行性挛缩、关节松弛的基础,并预测沉积在肌肉中的异常ECM的性质。为了研究肌无力的分子基础,我们正在开发一种新的共培养系统,其中各种患者来源的成纤维细胞培养物为正常肌肉细胞提供ECM。该系统将用于检查正常和突变的胶原VI基质对培养物中的肌管的影响。它将使我们能够确定导致肌肉功能障碍和肌肉细胞死亡的途径。最终,我们希望了解ECM对肌营养不良症发展的影响。有关这些途径的知识是在这一新的重要肌肉疾病组中制定有效治疗策略的先决条件。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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专利数量(0)
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CARSTEN G BONNEMANN其他文献
CARSTEN G BONNEMANN的其他文献
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{{ truncateString('CARSTEN G BONNEMANN', 18)}}的其他基金
Therapeutic Targets for the Congenital Muscular Dystrophies
先天性肌营养不良症的治疗目标
- 批准号:
8153397 - 财政年份:2009
- 资助金额:
$ 35.66万 - 项目类别:
The Molecular Basis of CMD Types Ullrich and Bethlem
Ullrich 和 Bethlem CMD 类型的分子基础
- 批准号:
7258453 - 财政年份:2005
- 资助金额:
$ 35.66万 - 项目类别:
The Molecular Basis of CMD Types Ullrich and Bethlem
Ullrich 和 Bethlem CMD 类型的分子基础
- 批准号:
6967291 - 财政年份:2005
- 资助金额:
$ 35.66万 - 项目类别:
The Molecular Basis of CMD Types Ullrich and Bethlem
Ullrich 和 Bethlem CMD 类型的分子基础
- 批准号:
7457960 - 财政年份:2005
- 资助金额:
$ 35.66万 - 项目类别:
The Molecular Basis of CMD Types Ullrich and Bethlem
Ullrich 和 Bethlem CMD 类型的分子基础
- 批准号:
7647345 - 财政年份:2005
- 资助金额:
$ 35.66万 - 项目类别:
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