Functions of ERK and p38 MAP Kinases in Astrogliosis

描述(申请人提供)：星形胶质细胞增生症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、癫痫障碍、多发性硬化症和神经退行性疾病。这种反应在再生过程中既有有益的作用，也有不利的作用。在某些情况下，广泛的星形胶质细胞增多症会阻碍大脑或脊髓功能的恢复。 拟议的研究计划的目标是阐明控制星形胶质细胞增生症的两个关键但未被研究的方面的细胞内机制：突起延长和细胞迁移。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群体。初步的体外数据表明，ERK和p38这两个MAP激酶通路对过程的延长和迁移起着不同的调节作用。重点将放在体内的新方法上，以测试这两个MAPK通路在星形胶质细胞损伤反应中的作用。 该项目的具体目标是： 1)星形胶质细胞突起延伸和迁移培养模型中ERK和p38MAPK信号的功能检测。 2)在脑和脊髓损伤的两种活体模型中，对ERK和p38MAPK信号在星形胶质细胞突起延伸和迁移中的功能进行了检测。 3)建立选择性激活星形胶质细胞的转基因模型：星形胶质细胞靶向的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为旨在抑制星形胶质细胞增生症的有害方面的治疗确定分子靶点。这种方法可以促进损伤或中风后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.