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的复杂反应：创伤、中风、癫痫发作、多发性硬化和神经退行性疾病。这种反应在再生中既有有利的作用，也有不利的作用。在某些情况下，脑或脊髓功能的恢复受到广泛的星形胶质细胞增生的阻碍。 拟议的研究计划的目标是阐明细胞内的机制，控制两个关键，但研究不足的方面星形胶质细胞增生：进程的扩展和细胞迁移。我们在小鼠脑中发现了一种新的损伤诱导的迁移性星形胶质细胞。初步的体外数据表明，两个MAP激酶途径，ERK和p38，差异调节过程的延伸和迁移。重点将放在新的体内方法来测试这两个MAP激酶通路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)ERK和p38 MAPK信号转导在星形胶质细胞突起延伸和迁移的培养模型中的功能测试。 2)ERK和p38 MAPK信号传导在星形胶质细胞过程延伸和迁移中的功能测试在脑和脊髓损伤的两种体内模型中引起。 3)选择性星形胶质细胞活化转基因模型的建立：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.