LAMININ ALPHA 2 IN TISSUE REGENERATION

层粘连蛋白 ALPHA 2 在组织再生中的作用

• 批准号: 6520939
• 负责人: EVA S ENGVALL
• 金额: $ 36.23万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6520939
• 关键词: Schwann cells; affinity chromatography; cell differentiation; disease /disorder model; gene expression; gene targeting; genetic models; genetically modified animals; integrins; laboratory mouse; laminin; model design /development; muscle proteins; muscular dystrophy; mutant; myogenesis; nervous system regeneration; peripheral nervous system; phenotype; protein isoforms; protein localization; protein structure function; regeneration; striated muscles; yeast two hybrid system

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.

描述：(改编自申请者摘要)组织再生与修复 对长寿至关重要。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的重要原因 肌肉和神经疾病以及年老的个体。层粘连蛋白亚基a2 在横纹肌和周围神经中显著表达，并且突变 在人类中引起一种严重形式的肌肉营养不良 (Merosin缺乏性先天性肌营养不良症)和小鼠。小鼠模型 对于人类来说，mcmd是通过用lacZ破坏lama2基因而产生的。 记者基恩。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的缺失不会显著影响 肌肉发生，但分化的层粘连蛋白A2缺陷肌肉高度 收缩时容易受伤的。最重要的是，与 明显的正常发育，再生严重受损 缺少层粘连蛋白A2。建议使用体内和体外模型来 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中进行分析。 组织特异性过表达人类LAMA2转基因的小鼠。要分析 骨骼成熟和存活的分子途径 肌肉和雪旺细胞、整合素和肌营养不良蛋白聚糖信号通路将 酵母双杂交筛选和亲和层析的特性 结合多肽质量图谱。拟议的研究将导致 肌肉和神经重要分子机制的新认识 可能有助于设计治疗退行性变的新策略 以促进再生为基础的肌肉和神经疾病。