GENE EXPRESSION IN BRAIN INJURY

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Trauma to the Central Nervous System (CNS) initiates a cascade of physiologic and molecular events that culminate in cellular injury and damage. Recent studies indicate that cells respond to trauma and other insults by altering the expression of specific genes. Among the genes expressed following CNS trauma are the immediate early genes (IEGs), many of which encode transcription factors. A second group of genes induced by CNS injury are those encoding heat-shock proteins (HSPs). Although the expression of these genes may be involved in the attempted recovery of function following brain trauma, little is known about the identity of the genes induced by trauma or the temporal/anatomic relationship between this induction and traumatic injury. Moreover, the consequences of post-traumatic induction of IEGs and HSPs remains poorly defined. This study will use molecular biology techniques to identify key changes in gene expression following experimental brain injury and relate these changes to histologic injury. Using in situ hybridization and immunohistochemistry, we will determine the timecourse and regional expression of several IEGs (c-fos, c-jun, junB, zif-268) in several models of brain trauma. We will then determine whether trauma-induced expression of IEGs is followed by expression of critical target genes, including proenkephalin, brain-derived neurotropic factor (BDNF), calbindin-D28K, and microtubule-associated protein (MAP2). We will also determine the timecourse and regional expression of hsp72, hsp90, and hsp32 (heme-oxygenase) following brain injury. Finally, we will correlate changes in gene expression with indicators of cell injury, including cellular calcium staining, blood-brain-barrier function, histologic damage and immunocytochemistry for glutamic acid decarboxylase (GAD). These studies will enhance our understanding of the cellular and molecular events following trauma and may lead to the development of novel targeted therapies for the treatment of traumatic brain injury.