Microglial mechanisms of postoperative CNS inflammation and cognitive decline

术后中枢神经系统炎症和认知能力下降的小胶质细胞机制

• 批准号: 9010611
• 负责人: Oleg Butovsky
• 金额: $ 49.97万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9010611
• 关键词: Abdomen; Ablation; Acute; Address; Affect; Age; Anesthesia procedures; Anesthetics; Bioinformatics; Biological; Biology; Blood; Brain; Cell Surface Proteins; Cells; Clinical; Cognitive; Data; Disease; Elderly; Fluorescence-Activated Cell Sorting; Functional disorder; General Anesthesia; Genes; Genetic Models; Immune; Impaired cognition; Inflammation; Inflammatory; Investigation; Isoflurane; Mediating; Methods; Microglia; Modeling; Molecular; Molecular Profiling; Monoclonal Antibodies; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Neurologic; Operative Surgical Procedures; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Population; Postoperative Period; Principal Investigator; Process; Property; Proteomics; Role; Series; Stress; Technology; Transforming Growth Factor beta; Work; age difference; age related; base; cognitive function; cost; experience; immune function; improved; in vivo; innovation; interest; macrophage; monocyte; novel; older patient; prevent; programs; public health relevance; response; senescence; therapeutic target; tool; transcriptome; young adult

 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.

 描述（由申请人提供）：本项目将研究小胶质细胞参与手术和全身麻醉后的认知障碍。认知功能障碍在老年手术患者中普遍存在且持续存在，并与较高的发病率和成本相关。病因不明，但与CNS炎症有关。小胶质细胞是中枢神经系统的免疫活性细胞，是中枢神经系统炎症的主要效应细胞，但直到最近，由于没有已知的编码细胞表面蛋白的小胶质细胞特异性基因，所以难以区分在应激期间浸润中枢神经系统的常驻小胶质细胞和髓样细胞。这是至关重要的，因为常驻小胶质细胞和浸润性巨噬细胞具有单独和不同的免疫功能。我们提出了一个转录组/蛋白质组/生物信息学的方法，使用最近发现的独特的小胶质细胞的分子签名，以调查年龄依赖性小胶质细胞生物学手术和麻醉期间和之后。使用这些工具，我们发现老年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稳态基因，并且异氟烷麻醉对年轻小鼠与老年小鼠中的小胶质细胞的影响不同。基于这些数据，我们提出，在旧的中枢神经系统的小胶质细胞磨损和失调是手术后认知功能障碍的脆弱性，手术。在这里，我们将确定手术和全身麻醉对小胶质细胞的分子和功能特征的影响;使用小胶质细胞消融/补充研究小胶质细胞对术后CNS炎症和认知障碍的贡献;并通过免疫调节小胶质细胞来挽救年龄依赖性的认知脆弱性。完成该项目后，我们将了解小胶质细胞分子和功能特性的年龄差异，驻留小胶质细胞与浸润性髓样胶质细胞在手术诱导的CNS炎症和认知下降中的作用，以及全身麻醉如何影响该过程，并确定了一种专门针对小胶质细胞的策略，以恢复其稳态分子特征，减少CNS炎症，并改善老年受试者的术后认知结果。重要的是，我们还将特异性靶向小胶质细胞，以恢复其稳态分子特征，从而减少CNS炎症并改善术后认知结果。这项工作是创新的，因为它使用最先进的方法和技术来探索老年患者术后认知功能下降的新的小胶质细胞机制，并且由于临床问题的规模和确定预防新方法的潜力而具有重要意义。