Functions of ERK and p38 MAP Kinases in Astrogliosis

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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.