Neurological Impact of Cardiopulmonary Bypass Surgery

心肺搭桥手术对神经系统的影响

• 批准号: 7140779
• 负责人: KEVIN Scott LEE
• 金额: $ 39.88万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140779
• 关键词: heart /lung bypass; hippocampus; injury; model; neurogenesis; neurogenetics; performance; surgery

DESCRIPTION (provided by applicant): The long-term neurological impact of cardio-pulmonary bypass (CPB) surgery can be profound. Recent studies indicate that significant cognitive decline is observed in 42% of CPB-patients when assessed five years after the procedure. This is a substantial biomedical problem because over 500,000 cardiac bypass procedures are performed each year in the United States. The underlying causes of CPB-induced cognitive decline are controversial and not well understood. The overall goal of this application is to characterize mechanisms of CPB-related injury and to evaluate a therapeutic strategy for treating long-term cognitive deficits after CPB. Our preliminary findings indicate that performance on a complex cognitive task is impaired for at least 5-6 months in a rat model of CPB. Studies under Aim #1 will characterize the behavioral impact of CPB in this replicable animal model, and will establish benchmarks for assessing long-term cognitive dysfunction after CPB. Aim #2 will examine three cellular mechanisms proposed to underlie CPB-induced injury: neuroinflammation, suppressed adult neurogenesis, and selective neuronal loss. Preliminary data indicate that sustained, localized neuroinflammation occurs in the hippocampus for at least 6 months after CPB. The preliminary findings also indicate that a substantial decrease in adult neurogenesis occurs in the area of neuroinflammation. These findings, which will be confirmed and extended under Aim #2, spur the hypothesis that sustained neuroinflammation in the hippocampus suppresses adult neurogenesis, which in turn produces long-term cognitive impairment. Aim #3 will test this concept by evaluating the protective effects of anti-inflammatory therapy on the neurogenetic and cognitive consequences of CPB. The benchmarks for behavioral impairment, established under Aim #1, will be used as a measure of cognitive function in these studies. It is hypothesized that blocking the inflammatory response to CPB will attenuate the suppression of neurogenesis and improve cognitive outcome. Together, the proposed studies will: 1) establish a means for assessing long-term cognitive deficits in a rodent recovery model of CPB, 2) characterize fundamental cellular mechanisms that underlie the deleterious effects of CPB, and 3) evaluate a specific therapeutic strategy for blocking and/or reversing cognitive decline associated with CPB. The results will expand our fundamental understanding of the mechanisms underlying CPB-related injury and will assess a rational candidate therapy for limiting cognitive decline after CPB.

描述（由申请人提供）：心肺转流（CPB）手术的长期神经影响可能是深远的。最近的研究表明，在手术后五年进行评估时，在42%的CPB患者中观察到显着的认知能力下降。这是一个重要的生物医学问题，因为在美国每年进行超过500，000次心脏搭桥手术。CPB引起的认知功能下降的根本原因是有争议的，并没有得到很好的理解。本申请的总体目标是表征CPB相关损伤的机制，并评价治疗CPB后长期认知缺陷的治疗策略。我们的初步研究结果表明，在CPB大鼠模型中，复杂认知任务的表现受损至少5-6个月。目标1下的研究将描述CPB在该可复制动物模型中的行为影响，并将建立评估CPB后长期认知功能障碍的基准。目标#2将研究三种被认为是CPB诱导损伤的细胞机制：神经炎症、抑制的成体神经发生和选择性神经元丢失。初步数据表明，持续的，局部的神经炎症发生在海马至少6个月后CPB。初步研究结果还表明，在成人神经发生的大幅减少发生在神经炎症领域。这些发现将在目标2下得到证实和扩展，刺激了海马中持续的神经炎症抑制成年神经发生的假设，这反过来又产生了长期的认知障碍。目标3将通过评价抗炎治疗对CPB的神经遗传学和认知后果的保护作用来测试这一概念。根据目标1建立的行为障碍基准将在这些研究中用作认知功能的衡量标准。假设阻断对CPB的炎症反应将减弱对神经发生的抑制并改善认知结果。总之，拟定的研究将：1）建立评估CPB啮齿动物恢复模型中长期认知缺陷的方法，2）表征CPB有害作用的基本细胞机制，3）评价阻断和/或逆转CPB相关认知下降的特定治疗策略。这些结果将扩大我们对CPB相关损伤机制的基本理解，并将评估限制CPB后认知功能下降的合理候选治疗。