Cognition and the immunology of postoperative outcomes

术后结果的认知和免疫学

• 批准号: 10404334
• 负责人: DEBORAH J CULLEY
• 金额: $ 32.19万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404334
• 关键词: Cognition; immunology; postoperative; outcomes

Program Director/Principal Investigator (Last, First, Middle): Culley, Deborah J ABSTRACT Surgery triggers a cascade of humoral, cellular, and subcellular events involved in inflammation and its resolution. These profound immune responses have a major influence on postoperative outcomes, and many complications of surgery are due to dysregulated inflammation. Older persons have more surgery than younger ones and are especially prone to serious postoperative morbidity. The immune system becomes dysregulated with age and this dysfunction contributes to the pathogenesis of age-related diseases, including cognitive decline. Poor cognition is a potent and consistent risk factor for adverse surgical outcomes; we have shown it doubles the risk of postoperative delirium and halves the chance of being discharged home after elective joint replacement surgery. We have also demonstrated that between 22-40% of elective surgical patients ≥ 70 years of age are probably cognitively impaired at the time of surgery. Therefore, the combination of poor preoperative cognition and poor surgical outcomes is both common and clinically important. Yet, it is not known how poor cognition increases susceptibility to postoperative morbidity, and the situation is little studied. We propose that poor preoperative cognition signifies a state of immune disequilibrium / dysfunction that shapes the immune response to surgery and increases postoperative morbidity. We will test this proposition by examining humoral (plasma inflammatory and resolution mediators; Aim 1), cellular (monocyte transcriptome and function; Aim 2), and subcellular (circulating extracellular vesicle [EV] concentration, cargo, and function; Aim 3) components of inflammation in cognitively screened patients having surgical procedures common in old age (total joint replacement; spine surgery), with delirium and discharge to place other than home as clinical and patient- centered-outcomes, respectively. Preliminary results showing cognition- or outcome-related differences in the ratio of circulating proinflammatory and proresolution mediators, the transcriptome of blood-borne monocytes, and the distribution of plasma extracellular vesicles support our model. This research is innovative because the impact of preoperative cognition on the immunology of surgical recovery has not been studied previously, it will test novel pathogenic mechanisms (monocyte dysfunction, EVs) for preoperative cognition-driven risk and use state-of-the-art ex vivo and in vitro methods (multiplexed gene panels), and may identify a molecular signature for adverse postoperative outcomes and, thereby, potential therapeutic targets. Given the magnitude and importance of the clinical problem being addressed, this is a high impact proposal that may increase the precision and personalization of surgical care and improve outcomes for older patients. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page

项目总监/首席研究员（最后，第一，中间）：Culley，Deborah J 抽象的 手术触发一系列炎症及其涉及的体液，细胞和亚细胞事件 解决。这些深刻的免疫反应对术后结果有重大影响，许多人 手术并发症是由于感染失调引起的。老年人的手术比年轻 尤其容易出现严重的术后发病率。免疫系统失调 随着年龄和这种功能障碍的促进与年龄相关疾病的发病机理，包括认知 衰退。认知不良是不良手术结果的潜在危险因素。我们已经显示了 将术后ir妄的风险增加一倍，并将选举联合后出院的机会减半 替代手术。我们还证明了22-40％的选择性手术患者≥70岁 在手术时，年龄可能会受到认知障碍。因此，术前差的结合 认知和手术结局差既常见又重要。然而，尚不知道多么贫穷 认知增加了术后发病率的敏感性，情况很少。我们提出了这一点 术前认知差表示塑造免疫的免疫diseSequilium /功能障碍状态 对手术的反应并增加术后发病率。我们将通过检查体液来测试该建议 （血浆炎症和分辨率介质； AIM 1），细胞（单核细胞转录组和功能； AIM 2）， 和亚细胞（循环细胞外囊泡[EV]浓度，货物和功能；目标3） 认知筛查的患者的炎症，该患者的外科手术程序常见于老年（总关节） 替代品;脊柱手术），del妄和放电以外的其他地方作为临床和患者 - 分别居中。初步结果显示了认知或结果相关的差异 循环促炎和前介介介质的比率，血传播单核细胞的转录组， 血浆细胞外蔬菜的分布支持我们的模型。这项研究具有创新性，因为 术前认知对手术恢复免疫学的影响以前尚未研究过，它将 测试术前认知驱动的风险和使用的新型致病机制（单核细胞功能障碍，EVS） 最先进的离体和体外方法（多重基因面板），可以识别分子特征 对于潜在的不良结果，从而导致潜在的治疗靶标。考虑到大小和 解决临床问题的重要性，这是一项高影响力，可能会增加 精确和个性化手术护理和改善老年患者的预后。 OMB编号0925-0001/0002（Rev. 03/16批准通过10/31/2018）页面延续格式页面