Functions of ERK and p38 MAP Kinases in Astrogliosis

描述（由申请人提供）：星形胶质细胞增生是星形胶质细胞对中枢神经系统损伤（创伤、中风、癫痫症、多发性硬化症和神经退行性疾病）的复杂反应。该反应被认为在再生中既有利又有害。在某些情况下，广泛的星形胶质细胞增生会阻碍大脑或脊髓功能的恢复。 拟议研究计划的目标是阐明控制星形胶质细胞增生的两个关键但尚未充分研究的方面的细胞内机制：过程延伸和细胞迁移。我们在小鼠大脑中发现了一种由损伤引起的迁移性星形胶质细胞的新群体。初步体外数据表明，ERK 和 p38 两种 MAP 激酶途径对过程延伸和迁移有差异性调节。重点将放在新的体内方法上，以测试这两种 MAP 激酶途径在星形胶质细胞对损伤的反应中的作用。 该项目的具体目标是： 1) 星形胶质细胞过程延伸和迁移培养模型中 ERK 和 p38 MAPK 信号传导的功能测试。 2) 在脑和脊髓损伤的两种体内模型中引发的星形胶质细胞过程延伸和迁移中的 ERK 和 p38 MAPK 信号传导的功能测试。 3）创建选择性星形胶质细胞激活的转基因模型：星形胶质细胞靶向条件成纤维细胞生长因子受体。 从这些研究中获得的知识可能会确定旨在抑制星形胶质细胞增生的有害方面的治疗的分子靶点。这种方法可以促进受伤或中风后大脑和脊髓功能的恢复。

DESCRIPTION (provided by applicant): Astrogliosis is the complex response of astrocytes to central nervous system injury: trauma, stroke, seizure disorders, multiple sclerosis and neurodegenerative disease. This reaction has been ascribed both beneficial and detrimental roles in regeneration. In some situations, recovery of brain or spinal cord function is impeded by extensive astrogliosis. The goal of the proposed research program is to elucidate intracellular mechanisms that control two key but understudied aspects of astrogliosis: process extension and cell migration. We have discovered a novel population of injury-induced migratory astroglia in the mouse brain. Preliminary in vitro data indicate that two MAP kinase pathways, ERK and p38, differentially regulate process extension and migration. The focus will be on novel in vivo approaches to testing roles for these two MAP kinase pathways in the astroglial response to injury. The specific aims of the project are: 1) Functional tests of ERK and p38 MAPK signaling in culture models of astroglial process extension and migration. 2) Functional tests of ERK and p38 MAPK signaling in astroglial process extension and migration elicited in two in vivo models of brain and spinal cord injury. 3) Creation of a transgenic model for selective astroglial activation: astroglial-targeted conditional fibroblast growth factor receptor. The knowledge obtained from these studies may identify molecular targets for therapies aimed at suppressing detrimental aspects of astrogliosis. This approach could promote recovery of brain and spinal cord function after injury or stroke.