A traumatic injury to the adult mammalian central nervous system (CNS), such as a stab wound injury, results in reactive astrogliosis and the migration of hematogenous cells into the damaged nervous tissue. It has been postulated that growth factors and cytokines locally released by the damaged endogenous cells play a major role in controlling cellular changes that occur following an injury. However, the exact roles of these signals remain to be elucidated. Astrocytes participate in a variety of physiologic and pathologic processes and reactive astrocytes have been shown to fulfill important functions in the CNS. They also express numerous factors that may be beneficial for promoting regeneration in the CNS. Chemokines, a novel class of chemoattractant cytokines, have recently been shown to participate in inflammatory processes that occur following injury in many kinds of tissues. A few studies have even demonstrated that chemokines play a role in the regulation of inflammatory cell invasion of the CNS and that astrocytes are the cellular source of these factors in certain CNS inflammatory diseases. However, the involvement of chemokines in the inflammatory process that occurs following traumatic injury to the CNS has not been elucidated. In the present proposal the investigators intend to study the time course for the expression of chemokines (MIP1 alpha, MIP1 beta, RANTES, MCP-1, IP10, and IL8) following stab wound injury in the mouse brain, and also determine whether astrocytes comprise the cellular source for their expression. To obtain a comprehensive understanding of the events that occur in stab wound injury, they will also study the expression of certain cytokines and growth factors that have been shown to participate in other pathophysiological phenomena if the CNS. The first specific aim proposes to determine mRNA levels of the factors (chemokines, cytokines and growth factors) in the mouse brain by reverse transcriptase/polymerase chain reaction (RT-PCR) at various times following stab wound injury. The second specific aim is to localize mRNAs of the factors in various cells which are differentially regulated at the various times following a stab wound injury by in situ hybridization with probes specific for the factors and cell specific antibodies. The third specific aim is to localize proteins for these factors in the various cells by double immunocytochemistry with factor- and cell- specific antibodies at the various times following stab wound injury. They hypothesize that these studies will lead to the identification of chemokines that may participate in the early events following a stab wound for the recruitment of hematogenous cells and also establish whether astrocytes are an important cellular source of these factors. Identification of the role of different cell types and specific factors released by these cells will be immensely helpful in understanding the course of events that occur during different stages of stab wound injury. Theses studies will also eventually aid in therapeutic intervention by identifying the factors and cells that will be required to be targeted and modulated in order to promote regeneration and enhance recovery.
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