Microglial mechanisms of postoperative CNS inflammation and cognitive decline

 描述(申请人提供)：这个项目将调查小胶质细胞参与手术和全身麻醉后的认知障碍。认知障碍在老年手术患者中普遍存在并持续存在，并与较高的发病率和成本相关。病因不明，但与中枢神经系统炎症有关。小胶质细胞是中枢神经系统炎症的主要效应细胞，是中枢神经系统的常驻免疫活性细胞，但直到最近，由于尚无编码细胞表面蛋白的小胶质细胞特异性基因，因此很难区分驻留的小胶质细胞和渗透到中枢神经系统应激的髓系细胞。这是至关重要的，因为驻留的小胶质细胞和浸润性巨噬细胞具有不同的和不同的免疫功能。我们提出了一种转录组/蛋白质组/生物信息学方法，利用最近发现的小胶质细胞独特的分子标记，在手术和麻醉期间和术后研究年龄相关的小胶质细胞生物学。使用这些工具，我们发现老年人大脑中的小胶质细胞较少，它们表达较低水平的免疫相关和内环境平衡基因，异氟醚麻醉对年轻小鼠和老年小鼠的小胶质细胞影响不同。基于这些数据，我们认为旧中枢神经系统的小胶质细胞磨损和调节失调是手术后和手术后易受认知障碍影响的原因。在这里，我们将确定手术和全身麻醉对小胶质细胞分子和功能特征的影响；通过小胶质细胞消融/补充来研究小胶质细胞在术后中枢神经系统炎症和认知功能障碍中的作用；通过免疫调节小胶质细胞来挽救手术和麻醉的年龄相关性认知易感性。项目完成后，我们将了解小胶质细胞的分子和功能特性的年龄差异，常驻的小胶质细胞和浸润性髓系细胞在手术诱导的中枢神经系统炎症和认知功能下降中的作用，以及全身麻醉如何影响这一过程，并定义了一种特定靶向小胶质细胞的策略，以恢复其体内平衡的分子特征，减少中枢神经系统炎症，并改善老年受试者的术后认知结果。重要的是，我们还将专门针对小胶质细胞来恢复它们的稳态分子特征，以减少中枢神经系统炎症，改善术后认知结果。提出的工作是创新的，因为它使用最先进的方法和技术来探索一种新的小胶质细胞机制，导致老年患者术后认知能力下降，而且由于临床问题的规模和寻找新的预防方法的潜力，这项工作具有重要意义。

 DESCRIPTION (provided by applicant): This project will investigate microglial involvement in cognitive impairment after surgery and general anesthesia. Cognitive impairment is prevalent and persistent in older surgical patients and associated with higher morbidity and cost. The cause is unknown but CNS inflammation is implicated. Microglia, the resident immune competent cells of the CNS, are major effectors of CNS inflammation, but until recently it was difficult to distinguish between resident microglia and myeloid cells that infiltrate the CNS durin stress because there were no known microglia specific genes encoding cell surface proteins. This is critical because resident microglia and infiltrating macrophages have separate and distinct immune functions. We propose a transcriptome / proteomincs / bioinformatics approach using a recently discovered unique molecular signature for microglia to investigate age-dependent microglia biology during and after surgery and anesthesia. Using such tools, we found there are fewer microglia in the old brain, that they express lower levels of immune-related and homeostatic genes, and that isoflurane anesthesia affects microglia in young vs. old mice differently. Based on these data, we propose microglial attrition and dysregulation in the old CNS are responsible for vulnerability to cognitive impairment after surgery and that surgery. Here we will identify the impact of surgery and general anesthesia on the molecular and functional signature of microglia; investigate the contribution of microglia to postoperative CNS inflammation and cognitive impairment using microglial ablation / replenishment; and rescue age-dependent cognitive vulnerability to surgery and anesthesia by immunomodulating microglia. Upon completion of the project, we will understand age differences in the molecular and functional properties of microglia, the role of resident microglia vs. infiltrating myeloid cels in surgery- induced CNS inflammation and cognitive decline, and how general anesthesia affects the process and defined a strategy for specifically targeting microglia to restore their homeostatic molecular signature, reduce CNS inflammation, and improve postoperative cognitive outcome in older subjects. Importantly, we will also specifically target microglia to restore their homeostatic molecular signature in order to reduce CNS inflammation and improve postoperative cognitive outcome. The work proposed is innovative because it uses state-of- the art methods and technology to explore a novel microglial mechanism for postoperative cognitive decline in older patients and significant because of the scale of the clinical problem and potential to identify new ways of preventing it.