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：
7393235
负责人：
Janice A Dominov
金额：
$ 35.88万
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/7393235
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）：先天性肌肉营养不良通常是由于肌肉纤维周围地下膜中层粘连蛋白A2（Merosin）表达不足引起的。缺乏梅罗蛋白的先天性肌肉营养不良（MCMD）的特征是出生后不久肌肉无力，这不足以显着改善以允许正常的卧床运动。 DY突变小鼠系也缺乏正常的层粘连蛋白U2表达，并为该疾病提供了实验模型。严重的突变体（例如DYW菌株）经历肌肉纤维变性，然后再生，但这些纤维死亡，涉及凋亡的过程。最终，小鼠在4个月大的时间内死亡。我们发现，Bcl-2（凋亡的抑制剂）的肌肉特异性过表达可以显着延长生存率Dyw小鼠并改善断奶后生长，从而表明在肌肉细胞中特别调节细胞死亡对这种疾病进展有巨大影响。此外，我们发现D/V动物缺乏Bax（一种相关的促凋亡蛋白）表现出更大的寿命和生长，以及与粘粘着层粘连蛋白A2缺陷髓鞘缺陷相关的后肢瘫痪减少。提出了实验，以进一步探索Bcl-2和Bax在层粘连蛋白A2缺陷肌肉病理学进展中的作用，并确定它们对疾病早期和后期阶段凋亡，再生和存活的影响。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在正常和层粘连蛋白A2缺乏的肌肉细胞中的表达。这些蛋白质的表达将在体内进行实验改变，以确定它们是否可以调节层粘连蛋白U2缺陷肌肉的存活率，以及是否可以通过改变其水平在不同阶段调节疾病进展。这些结果将进一步理解控制层粘连蛋白A2缺陷肌肉变性过程中凋亡过程的机制，并可能确定可以作为治疗人MCMD治疗治疗的靶标的途径。