ASTROCYTE RESPONSE TO TRAUMA--MECHANISM AND SIGNIFICANCE

University Of Miami School Of Medicine, Coral Gables FL

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Abstract

Astrocytes constitute a major cell that contributes to the heterogeneous and complex response to brain trauma. The mechanism and significance of the glial response to injury are not fully understood. Our working hypothesis is that direct physical injury to astrocytes initially alters the basic properties and functions of astrocytes, which may be subsequently modified by secondary factors related to trauma. We believe that initially glial functions are impaired, but that these cells subsequently recover and generate factors which are beneficial for CNS recovery. Our overall plan is to critically examine the temporal profile of the various changes that occur in astrocytes following trauma. Our principal strategy will involve the use of an in vitro model of fluid percussion injury (FPI). Where appropriate, our findings will be correlated with in vivo studies using a FPI model established by our colleagues in the Program Project. We plan to accomplish the following aims: 1) investigate basic cellular properties of traumatized astrocytes by examining cell morphology, proliferative capacity, GFAP content, RNA and protein synthesis, and energy metabolism (levels of energy metabolites, oxygen and glucose utilization). 2) Examine the functional state of astrocytes by determining the kinetics of glutamate and K+ uptake and as well as measure mRNA and protein levels of the glial glutamate transporters (GLT-1 and GLAST). We will also conduct in situ hybridization studies on the glial glutamate transporters using an in vivo model of fluid percussion injury. Also, we will examine the ability of traumatized astrocytes to generate growth factors (NGF, bFGF). 3) Examine the role of calcium in trauma-induced glial swelling by focusing on the relationship between calcium flux and free intracellular calcium content with the extent of glial swelling, the mechanism of Ca2+ entry and mobilization, and the effects of protein kinases on cell volume following trauma. 4) investigate the effect of trauma-derived secondary factors (e.g., glutamate, lactic acid, free radicals, nitric oxide, cytokines, arachidonic acid, anoxia, hyperthermia) on traumatized astrocytes. We postulate that traumatized astrocytes become sensitized to the effects of secondary agents, or that secondary factors will exert additive effects. We believe that these studies will provide a better understanding of the role of astrocytes in brain trauma, and will yield important information that may ultimately influence the outcome of repair and regeneration in the CNS.