Neurological Impact of Cardiopulmonary Bypass Surgery

心肺搭桥手术对神经系统的影响

• 批准号: 7243333
• 负责人: KEVIN Scott LEE
• 金额: $ 33.1万
• 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/7243333
• 关键词: Address; Adult; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Area; Attenuated; Behavioral; Benchmarking; Brain; Bypass; Cardiac; Cardiopulmonary Bypass; Cell Death; Cells; Cognitive; Cognitive deficits; Complex; Count; Data; Development; Diffuse; Early Intervention; Event; Functional disorder; Future; Goals; Hippocampus (Brain); Impaired cognition; Impairment; Inflammation; Inflammatory Response; Injury; Knowledge; Lead; Life; Localized; Lung; Measures; Mediating; Memory; Memory impairment; Microglia; Modeling; Molecular; Nature; Nerve Degeneration; Nervous System Trauma; Neuraxis; Neurologic; Neurons; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Outcome; Outcome Measure; Patients; Performance; Play; Procedures; Protocols documentation; Rattus; Recovery; Rodent; Role; Techniques; Testing; Therapeutic; Time; Treatment Efficacy; Treatment Protocols; United States; Upper arm; base; behavior test; cognitive function; comparison group; concept; functional decline; gliogenesis; improved; middle age; neurogenesis; neurogenetics; neuroinflammation; neuron loss; novel; protective effect; research study; response

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）：心肺旁路（CPB）手术的长期神经系统影响可能是深刻的。最近的研究表明，在手术后五年评估时，在42％的CPB患者中观察到了显着认知能力下降。这是一个实质性的生物医学问题，因为在美国，每年进行500,000多个心脏旁路程序。 CPB引起的认知能力下降的根本原因是有争议的，尚未得到充分理解。该应用的总体目标是表征与CPB相关损伤的机制，并评估CPB后治疗长期认知缺陷的治疗策略。我们的初步发现表明，在CPB的大鼠模型中，至少5-6个月会损害复杂的认知任务的表现。 AIM＃1的研究将表征CPB在此可复制动物模型中的行为影响，并将建立用于评估CPB后长期认知功能障碍的基准。 AIM＃2将检查提出的三种细胞机制，以构成CPB诱导的损伤：神经炎症，抑制成人神经发生和选择性神经元丧失。初步数据表明，在CPB后至少6个月内，海马中发生了持续的局部神经炎症。初步发现还表明，在神经炎症区域中，成年神经发生大幅下降。这些发现将在AIM＃2下进行确认和扩展，刺激了海马中持续神经炎症的假设抑制了成人神经发生，这又会产生长期的认知障碍。 AIM＃3将通过评估抗炎疗法对CPB神经发生和认知后果的保护作用来测试这一概念。在AIM＃1下建立的行为障碍的基准将用作这些研究的认知功能的量度。假设阻止对CPB的炎症反应会减轻神经发生的抑制并改善认知结果。拟议的研究将共同​​：1）建立一种用于评估CPB啮齿动物恢复模型中的长期认知缺陷的方法，2）表征基本的细胞机制，这些机制是CPB的有害影响的基础，以及3）评估特定的治疗策略，用于阻断和/或逆转与CPB相关的认知能力。结果将扩大我们对与CPB相关损伤基础机制的基本理解，并将评估一种合理的候选疗法，以限制CPB后认知能力下降。