LAMININ ALPHA 2 IN TISSUE REGENERATION

描述：（改编自申请人摘要）组织再生和修复 是长寿的关键肌肉和神经再生不足是一种 肌营养不良和其他疾病患者发病重要原因 肌肉和神经疾病以及衰老个体。层粘连蛋白亚基a2 在横纹肌和周围神经中显著表达， 在lama2基因中导致人类严重的肌肉萎缩症 （裂殖蛋白缺陷型先天性肌营养不良症，MCMD）和小鼠。小鼠模型 通过用lacZ破坏lama2基因来产生人MCMD 报告基因纯合子突变小鼠发生肌营养不良和外周 出生后的神经病层粘连蛋白a2的缺乏并不显著影响 肌生成，但分化层粘连蛋白A2缺陷的肌肉高度 在收缩时容易受伤。最重要的是， 表面上正常的发展，再生严重受损， 缺乏层粘连蛋白A2。建议使用体内和体外模型， 分析骨骼肌和周围神经的发育和再生， 确定再生过程中的哪些步骤依赖于层粘连蛋白A2。 层粘连蛋白a2的再生促进作用将在转基因小鼠中进行分析。 具有人LAMA2转基因的组织特异性过表达的小鼠。分析 负责骨骼肌成熟和存活的分子途径 肌肉和许旺细胞，整合素和肌营养不良蛋白聚糖信号通路将被 其特征在于采用酵母双杂交筛选和亲和层析， 结合肽质量作图。这项研究将导致 关于肌肉和神经的重要分子机制的新知识 功能，并可能有助于制定新的战略，治疗退行性疾病 基于促进再生的肌肉和神经疾病。

DESCRIPTION: (Adapted from applicant's abstract) Tissue regeneration and repair are critical to longevity. Insufficient regeneration of muscle and nerve is a significant cause of morbidity in patients with muscular dystrophy and other muscle and nerve diseases and in the aging individual. The laminin subunit a2 is prominently expressed in striated muscle and peripheral nerve, and mutations in the lama2 gene cause a severe form of muscular dystrophy in humans (merosin-deficient congenital muscular dystrophy, MCMD) and mice. A mouse model for human MCMD was generated by disrupting the lama2 gene with the lacZ reporter gene. Homozygous mutant mice develop muscular dystrophy and peripheral neuropathy after birth. Absence of laminin a2 does not significantly affect myogenesis, but the differentiated laminin a2-deficient muscle are highly susceptible to injury upon contraction. Most important, in contrast to the apparent normal development, regeneration is severely compromised in the absence of laminin a2. It is proposed to use in vivo and in vitro models to analyze development and regeneration of skeletal muscle and peripheral nerve to determine which steps in the regeneration process are dependent on laminin a2. The regeneration-promoting effects of laminin a2 will be analyzed in transgenic mice with tissue-specific overexpression of a human LAMA2 transgene. To analyze the molecular pathways responsible for maturation and survival of skeletal muscle and Schwann cells, integrin and dystroglycan signaling pathways will be characterized by using the yeast 2-hybrid screening and affinity chromatography in combination with peptide mass mapping. The proposed research will result in new knowledge regarding important molecular mechanisms of muscle and nerve function and may help in devising new strategies for treatment of degenerative diseases of muscle and nerve based on promoting regeneration.