Pathogenesis of Laminin-alpha2 Deficiency

描述（由申请人提供）：lamininot2缺乏症的发病机制。人类LAMA2基因突变导致先天性肌营养不良，1组（CMD 1），一种毁灭性的儿童隐性疾病。LAMA2编码层粘连蛋白c β 2，这是一种在骨骼肌中丰富的细胞外蛋白。所提出的实验将验证关于层粘连蛋白-c_2的丢失如何导致CMD1严重神经肌肉功能障碍的假设。在目的1和目的2中，我们将研究细胞凋亡在CMD1发病机制中的作用。在培养中，laminin-cz2缺陷肌管不稳定，并通过抗凋亡蛋白Bcl-2抑制的过程死亡。然而，尚不清楚细胞凋亡在体内CMD1神经肌肉功能丧失中是否重要。拟议的实验将确定Bcl-2家族成员的靶向改变如何影响层粘连蛋白-c_2缺陷小鼠的疾病。

DESCRIPTION (provided by applicant): Pathogenesis of laminin-ot2-deficiency. Mutations in the human LAMA2 gene cause congenital muscular dystrophy, group 1 (CMD 1), a devastating, recessive disease of childhood. LAMA2 encodes laminin-c Beta 2, an extracellular protein that is abundant in skeletal muscle. The proposed experiments will test hypotheses about how loss of laminin-c_2 leads to the severe neuromuscular dysfunction in CMD1. For Aims 1 & 2, we will examine the role of apoptosis in CMD1 pathogenesis. In culture, laminin-cz2-deficient myotubes are unstable and die by a process that is inhibited by the antiapoptosis protein Bcl-2. It is not known, however, whether apoptosis is important in the loss of CMD1 neuromuscular function in vivo. The proposed experiments willdetermine how disease in laminin-c_2-deficient mice is affected by targeted alterations of Bcl-2 family members. For Aim 3, we will determine if muscle stem cell function is altered in CMD 1. Postnatal muscle contains multipotent stem cells, but no studies have examined these recently identified stem cells in diseased muscle. We will test the possibility that laminin- Beta 2-deficiency activates proliferation and alters the differentiation capability of these rare cells. For Aim 4, we will determine if inappropriate re-entry into the cell cycle occurs in affected tissue. Inappropriate cell cycling can lead to death of normally post-mitotic cells including neurons and myofibers. We hypothesize that laminin-cz2-deficiency alters signal transmission resulting in dysregulation of the cell cycle. To test this hypothesis, we will determine if cell cycle regulators are inappropriately induced in laminin-c beta 2-deficient cells. The results will increase our understanding of CMD 1 pathogenesis and could suggest new routes to therapy, perhaps based on apoptosis inhibition, stem cell repair, or cell cycle inhibition.