ROLE OF LEUKOCYTE ADHESION IN CNS ISCHEMIC INJURY

白细胞粘附在中枢神经系统缺血性损伤中的作用

• 批准号: 3084589
• 负责人: WAYNE M CLARK
• 金额: $ 9.37万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-01-15 至 1995-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3084589
• 关键词: antibody; central nervous system; cerebral ischemia /hypoxia; disease /disorder model; drug adverse effect; immunotherapy; laboratory rabbit; leukocyte adhesion molecules; model design /development; monoclonal antibody; neutrophil; nonhuman therapy evaluation; surface antigens

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.

本提案中概述的培训和研究计划支持 为 Dr. 申请 NINDS 临床研究者发展奖 韦恩·克拉克。拟议的项目将使克拉克博士能够在 在 Bruce Coull 博士的直接监督下，成为一名训练有素的研究员 具有脑血管疾病方面的专业知识。 拟议五年研究的总体目标 该奖项旨在研究白细胞粘附在中枢神经系统缺血中的作用 受伤。提出的实验基于三个主要假设 先前的研究支持：1）白细胞是积极的参与者 神经元缺血性损伤； 2）他们的参与需要白细胞 粘合性能； 3) 可以通过以下方式减少其不利影响 使用新疗法，白细胞抗粘附抗体（抗CD 18）。两人 此 CIDA 应用程序的主要目标是 1) 研究关系 白细胞和中枢神经系统缺血之间的关系，2) 确定白细胞是否 抗粘连抗体治疗可有效减少中枢神经系统损伤。到 为了实现这些目标，建议进行以下实验： 将使用过滤测量白细胞流变特性 技术。使用选择性实验性中枢神经系统缺血模型 重复测量设计将用于比较基线流变学 测量在有或没有缺血的动物中获得的结果 抗CD 18治疗。 白细胞浸润缺血中枢神经系统组织的时间和程度 将使用实验性中枢神经系统缺血模型进行评估。直接的 组织学评估将比较有或没有抗 CD 的缺血动物 18 治疗。 抗CD 18治疗的疗效将在以下方面进行评估： 实验性可逆大血管中枢神经系统缺血模型。该模型将 测试抗CD 18减少再灌注损伤的能力（无回流 现象）。 抗CD 18治疗的疗效将在以下方面进行评估： 实验性不可逆微血管中枢神经系统缺血模型。该模型将 测试抗CD 18改善缺血部位血流的能力 半影。 上述研究结果有望证实其积极作用 白细胞的减少加剧了中枢神经系统缺血性损伤。如果抗CD 18治疗 能有效减少中枢神经系统再灌注损伤，它提供了巨大的 作为临床中风治疗的潜力，特别是考虑到目前 临床上应用溶栓剂。