Apoptosis in Laminin alpha2-Deficient Muscle Pathology

先天性肌营养不良通常是由于脑组织中层粘连蛋白a2(Merosin)表达不足引起的 肌纤维周围的基底膜。硫球蛋白缺乏型先天性肌营养不良 (Mcmd)的特征是出生后不久就出现严重的肌肉无力，而且没有改善。 足够明显，可以进行正常的活动。Dy突变的小鼠品系也缺乏正常 层粘连蛋白U2的表达，为本病提供实验模型。严重的突变，如 Dyw菌株经历了肌肉纤维的退化和再生，但这些纤维在 涉及细胞凋亡的过程。最终，老鼠会在4个月内死亡。我们已经找到了那块肌肉- 细胞凋亡抑制因子Bcl2的特异性过表达可显著延长生存期 并改善断奶后的生长，从而表明调节细胞死亡的特异性在 肌肉细胞对这种疾病的进展有很大的影响。此外，我们发现D/V动物 缺乏Bax，一种相关的促凋亡蛋白，表现出更长的寿命和生长 与层粘连蛋白A2缺乏性髓鞘形成缺陷相关的后肢瘫痪减轻。实验是 建议进一步探讨Bcl2和Bax在层粘连蛋白A2缺陷性肌病发生发展中的作用 病理学，并确定它们在早期和晚期对细胞凋亡、再生和存活的影响 疾病的各个阶段。我们还将研究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。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缺陷的肌肉以及疾病进展是否可以在不同的阶段通过 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缺陷性肌肉退变过程中的细胞凋亡过程及可能识别的途径 可作为人类MCMD治疗干预的靶点。

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.