Apoptosis in Laminin alpha2-Deficient Muscle Pathology

层粘连蛋白 α2 缺陷的肌肉病理学中的细胞凋亡

• 批准号: 7424110
• 负责人: Janice A Dominov
• 金额: $ 0.6万
• 依托单位: BOSTON BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7424110
• 关键词: Accounting; Activation Analysis; Affect; Age of Onset; Age-Months; Animals; Apoptosis; Apoptotic; BIRC4 gene; Basement membrane; Bax protein; Birth; CD8-Positive T-Lymphocytes; Caspase; Cell Death; Cell Proliferation; Cell Survival; Cells; Cessation of life; Critical Pathways; Defect; Disease; Disease Progression; Disease model; Exhibits; Experimental Models; Fiber; Future; Genes; Growth; Hindlimb; Histology; Human; Immunohistochemistry; In Situ Nick-End Labeling; In Vitro; Inflammatory; Inflammatory Response; Inhibition of Apoptosis; Laminin; Limb structure; Longevity; Merosin; Methods; Motion; Mouse Strains; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle Weakness; Mutant Strains Mice; Mutation; Myopathy; Natural regeneration; Numbers; Paralysed; Pathogenesis; Pathology; Pathway interactions; Pattern; Population; Prevalence; Process; Protein Family; Protein Overexpression; Proteins; RNA Interference; Range; Regulation; Repression; Research Personnel; Role; Severities; Skeletal Muscle; Staging; Symptoms; TNF gene; Tenascin; Therapeutic Intervention; Tissues; Transgenes; Transgenic Organisms; Viral; Weaning; Week; Western Blotting; apoptotic protease-activating factor 1; congenital muscular dystrophy; day; design and construction; genetic regulatory protein; human BIRC3 protein; improved; in vivo; in vivo regeneration; macrophage; mutant; myelination; precursor cell; pro-apoptotic protein; programs; protein expression; research study; size

Congenital muscular dystrophy is often caused by deficiency in laminin a2 (merosin) expression in the basement membrane surrounding muscle fibers. Merosin-deficient congenital musculardystrophy (MCMD) is characterized by severe muscle weakness shortly after birth that does not improve significantly enough to allow normal ambulatory motion. The dy mutant mouse lines also lack normal laminin u2 expression and provide and experimental models for this disease. Severe mutants such as the dyw strain undergo muscle fiber degeneration followed by regeneration, but these fibers die in a process involving apoptosis. Ultimately mice die within 4 months of age. We have found that muscle- specific overexpression of Bcl-2 (an inhibitor of apoptosis) can significantly prolong the survival dyw mice and improve post-weaning growth thus indicating that regulation of the cell death specifically in muscle cells has a dramatic effect on this disease progression. Additionally, we find that d/v animals deficient in Bax, a related pro-apoptotic protein, exhibit even greater longevity and growth along with reduced hindlimb paralysis associated with laminin a2- deficient myelination defects. Experiments are proposed to further explore the role of Bcl-2 and Bax in the progression of laminin a2-deficient muscle pathology and determine their effects on apoptosis, regeneration and survival at both early and later stages of disease. We will also examine expression of other apoptotic regulatory molecules, specifically FLIPL, ARC,XIAP, and Apaf-1, in normal and laminin a2-deficient muscle cells. Expression of these proteins will be experimentally altered in vivo to determine whether or not they can regulate the survival of laminin u2-deficient muscle and if disease progression can be modulated at different stages by altering their levels. These results will further our understanding of mechanisms controlling the apoptotic process during laminin a2-deficient muscle degeneration and possibly identify pathwaysthat could serve as targets for therapeutic intervention in the treatment of human MCMD.

先天性肌营养不良症通常是由肌纤维中层粘连蛋白a2（merosin）表达缺陷引起的。 肌纤维周围的基底膜。裂殖蛋白缺乏型先天性肌营养不良 （MCMD）的特征是出生后不久出现严重的肌肉无力， 足以允许正常的走动运动。dy突变小鼠品系也缺乏正常的 层粘连蛋白U2表达，并为该疾病提供实验模型。严重的突变体，如 dyw品系经历肌纤维变性，然后再生，但是这些纤维以 涉及凋亡的过程。最终小鼠在4个月内死亡。我们发现了那块肌肉- Bcl-2（一种凋亡抑制剂）的特异性过表达可以显著延长存活时间， 小鼠和改善断奶后生长，从而表明细胞死亡的调节特异地 肌肉细胞对这种疾病的进展有着巨大的影响。此外，我们发现d/v动物 Bax（一种相关的促凋亡蛋白）缺乏的小鼠表现出更长的寿命和生长沿着 减少与层粘连蛋白A2缺陷髓鞘形成缺陷相关的后肢瘫痪。实验 提出进一步探讨Bcl-2和Bax在层粘连蛋白a2缺陷的肌肉进展中的作用， 病理学，并确定其对细胞凋亡，再生和存活的影响，在早期和后期 疾病的阶段。我们还将检测其他凋亡调节分子的表达，特别是 FLIPL、ARC、XIAP和Apaf-1，在正常和层粘连蛋白a2缺陷的肌肉细胞中。表达这些 蛋白质将在体内进行实验性改变，以确定它们是否可以调节存活 层粘连蛋白u2缺乏的肌肉以及疾病进展是否可以在不同阶段通过以下方式调节 改变他们的水平。这些结果将进一步加深我们对控制细胞凋亡的机制的理解。 层粘连蛋白A2缺陷性肌肉变性过程中的细胞凋亡过程，并可能确定 可以作为治疗人MCMD的治疗性干预的靶点。