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: 3084587
• 负责人: WAYNE M CLARK
• 金额: $ 8.36万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 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/3084587
• 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 申请NINDS临床研究人员发展奖。 韦恩·克拉克。拟议的项目将使克拉克博士能够在 布鲁斯·库尔博士的直接监督，成为一名训练有素的研究人员 在脑血管疾病方面有专长。 这项研究的总体目标建议为以下五年 该奖项旨在研究白细胞黏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 以前的研究支持：1)白细胞是活跃的参与者 在神经元缺血性损伤中；2)它们的参与需要白细胞 粘接性；以及，3)它们的不良影响可以通过 使用一种新的治疗方法，白细胞抗黏附抗体(抗CD18)。两个人 本CIDA申请的主要目的是1)研究 白细胞与中枢神经系统缺血之间的关系2)确定白细胞是否 抗黏附抗体治疗能有效减轻中枢神经系统损伤。至 为了实现这些目标，建议进行以下实验： 白细胞的流变性将通过过滤进行测量 技巧。利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 对有或无缺血动物实验结果的测量 抗CD18治疗。 中枢神经系统缺血组织中白细胞浸润的时间和程度 将使用实验性中枢神经系统缺血模型进行评估。直接 组织学评估将比较使用和不使用抗CD抗体的缺血动物 18个疗程。 抗CD18治疗的疗效将在一项 实验性可逆性大血管中枢神经系统缺血模型。这款车型将 检测抗CD18抗体对再灌注损伤(无复流)的保护作用 现象)。 抗CD18治疗的疗效将在一项 实验性中枢神经系统不可逆微血管缺血模型。这款车型将 检测抗CD18抗体改善脑缺血区血流的能力 半影区。 上述研究的结果有望证实这一积极作用 白细胞在加重中枢神经系统缺血性损伤中的作用。If抗CD18治疗 在减少中枢神经系统再灌注损伤方面有效，它提供了巨大的 作为一种临床中风疗法的潜力，特别是考虑到目前 溶栓剂的临床应用。