The training and research program outlined in this proposal supports the application for an NINDS Clinical Investigator Development Award for Dr. Wayne Clark. The proposed project will enable Dr. Clark to develop, under the direct supervision of Dr. Bruce Coull, into a well trained researcher with an expertise in cerebrovascular disease. The overall objective of the research proposed for the five year period of the award is to investigate the role of leukocyte adhesion in CNS ischemic injury. The experiments proposed are based on three major hypotheses supported by previous studies: 1) that leukocytes are active participants in neuronal ischemic injury; 2) that their involvement requires leukocyte adhesive properties; and, 3) that their adverse effects can be reduced by using a new therapy, leukocyte anti-adhesion antibody (anti-CD 18). The two main objectives of this CIDA application are to 1) study the relationship between leukocytes and CNS ischemia and 2) determine if leukocyte anti-adhesion antibody treatment is effective in reducing CNS injury. To accomplish these objectives, the following experiments are proposed: Leukocyte rheologic properties will be measured using filtration techniques. Using a model of selective experimental CNS ischemia, a repeated measures design will be used to compare baseline rheologic measurements to results obtained in ischemic animals with or without anti-CD 18 treatment. The timing and extent of leukocyte infiltration into ischemic CNS tissue will be assessed using an experimental CNS ischemia model. Direct histologic evaluation will compare ischemic animals with or without anti-CD 18 treatment. The therapeutic efficacy of anti-CD 18 treatment will be assessed in an experimental reversible large vessel CNS ischemia model. This model will test the ability of anti-CD 18 to reduce reperfusion injury (no reflow phenomenon). The therapeutic efficacy of anti-CD 18 treatment will be assessed in an experimental irreversible microvascular CNS ischemia model. This model will test the ability of anti-CD 18 to improve blood flow to the ischemic penumbra. The results from the above studies are expected to confirm the active role of leukocytes in exacerbating CNS ischemic injury. If anti-CD 18 treatment is effective at reducing CNS reperfusion injury, it offers tremendous potential as a clinical stroke therapy, particularly given the current clinical use of thrombolytic agents.
