In this proposal we seek a better understanding of the processes involved in the regulation of postischemic DNA damage, DNA repair and apoptosis. Our overall goals are: to reduce apoptosis after cerebral ischemia in the rat, to investigate the effects of post ischemic inflammatory response on apoptosis, and as a therapeutic intervention to reduce apoptosis by selectively blocking adhesion molecules (CD11b, ICAM-1).
Two Specific Aims are presented:
Aim 1. 1: To measure the temporal profile and anatomical distribution of apoptotic and inflammatory cells in rat brain subjected mild (0.5 h) and severe (2 h) transient middle cerebral artery occlusion (MCAo). 1.2 To identify cell types of intact, injured and apoptotic cells as a function of time after transient MCAo. 1.3 To identify within ischemic tissue protein expression that may direct the cell to select an apoptotic response to a transient ischemic insult, particularly: proteins associated with DNA damage, DNA repair, and cell cycle.
Aim 2. 1: To measure the effect of administration of anti-adhesion molecule antibodies on apoptotic cells and inflammatory cells after transient MCAo. 2.2 to determine whether neutrophils contribute to apoptosis by measuring apoptotic cells in neutropenic rats subjected to MCAo. 2.3 To determine whether T cells contribute to apoptosis, by measuring apoptotic cells in athymic nude rats subjected to MCAo. 2.4 To determine whether monocytes and microglia contribute to apoptosis, by measuring apoptotic cells in rats subjected to MCAo and administered chloroquine and colchicine, agents which suppress the biological activity of mononuclear phagocytes. Our studies will clarify the molecular mechanisms contributing to apoptosis in ischemic brain and improve our understanding of the apoptotic events associated with the post ischemic immune/inflammatory cascade.
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