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：
7216337
负责人：
Janice A Dominov
金额：
$ 36.61万
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/7216337
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 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

DESCRIPTION (provided by applicant): Congenital muscular dystrophy is often caused by deficiency in laminin a2 (merosin) expression in the basement membrane surrounding muscle fibers. Merosin-deficient congenital muscular dystrophy (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 an 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 hind limb 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 pathways that could serve as targets for therapeutic intervention in the treatment of human MCMD.

描述（由申请人提供）：先天性肌营养不良症通常是由肌纤维周围的基底膜中层粘连蛋白 a2（merosin）表达缺陷引起的。梅罗蛋白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，且没有明显改善，无法进行正常的走动运动。 dy 突变小鼠系也缺乏正常的层粘连蛋白 u2 表达，并为这种疾病提供了实验模型。诸如 dyw 菌株等严重突变体会经历肌纤维变性，然后再生，但这些纤维在涉及细胞凋亡的过程中死亡。最终小鼠在 4 个月龄内死亡。我们发现肌肉特异性过度表达 Bcl-2（细胞凋亡抑制剂）可以显着延长 dyw 小鼠的存活时间并改善断奶后的生长，因此表明肌肉细胞中细胞死亡的调节对该疾病的进展具有显着影响。此外，我们发现缺乏 Bax（一种相关的促凋亡蛋白）的 d/v 动物表现出更长的寿命和生长，同时减少与层粘连蛋白 a2 缺陷髓鞘形成缺陷相关的后肢麻痹。拟进行实验以进一步探讨 Bcl-2 和 Bax 在层粘连蛋白 a2 缺陷型肌肉病理进展中的作用，并确定它们在疾病早期和晚期对细胞凋亡、再生和存活的影响。我们还将检查正常和层粘连蛋白 a2 缺陷的肌肉细胞中其他凋亡调节分子的表达，特别是 FLIPL、ARC、XIAP 和 Apaf-1。这些蛋白质的表达将在体内通过实验改变，以确定它们是否可以调节层粘连蛋白u2缺陷肌肉的存活，以及是否可以通过改变其水平在不同阶段调节疾病进展。这些结果将进一步加深我们对层粘连蛋白 a2 缺陷型肌肉变性过程中控制细胞凋亡过程的机制的理解，并可能确定可作为人类 MCMD 治疗干预目标的途径。