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

基本信息

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
项目类别：
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

项目摘要

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层粘连蛋白 a2（merosin）表达缺陷引起的肌纤维周围有基底膜。 Merosin 缺陷型先天性肌营养不良症 (MCMD) 的特点是出生后不久出现严重的肌肉无力且没有改善明显足以允许正常的行走运动。 dy突变小鼠系也缺乏正常的层粘连蛋白u2的表达并提供了该疾病的实验模型。严重突变体如 dyw 菌株经历肌纤维退化，然后再生，但这些纤维会在涉及细胞凋亡的过程。最终小鼠在 4 个月龄内死亡。我们发现肌肉—— Bcl-2（细胞凋亡抑制剂）的特异性过度表达可显着延长 dyw 的生存期小鼠并改善断奶后的生长，从而表明细胞死亡的调节特别是在肌肉细胞对这种疾病的进展有巨大的影响。此外，我们发现 d/v 动物缺乏 Bax（一种相关的促凋亡蛋白）时，会表现出更长的寿命和生长速度减少与层粘连蛋白 a2 缺乏性髓鞘形成缺陷相关的后肢麻痹。实验是建议进一步探讨 Bcl-2 和 Bax 在层粘连蛋白 a2 缺陷肌肉进展中的作用病理学并确定其对早期和晚期细胞凋亡、再生和存活的影响疾病的阶段。我们还将检查其他凋亡调节分子的表达，特别是 FLIPL、ARC、XIAP 和 Apaf-1，存在于正常和层粘连蛋白 a2 缺陷的肌肉细胞中。这些的表达蛋白质将在体内进行实验改变，以确定它们是否可以调节生存层粘连蛋白 u2 缺乏的肌肉以及是否可以通过以下方式在不同阶段调节疾病进展：改变他们的水平。这些结果将进一步加深我们对控制机制的理解层粘连蛋白 a2 缺陷型肌肉变性期间的细胞凋亡过程，并可能确定以下途径：可以作为人类 MCMD 治疗干预的目标。