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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：该项目将研究手术和全身麻醉后认知障碍的小胶质细胞受累。认知障碍在老年手术患者中普遍存在并且持续存在，并且与发病率和成本更高有关。原因是未知的，但中枢神经系统感染涉及。小胶质细胞是中枢神经系统的驻留免疫能力细胞，是中枢神经系统感染的主要作用，但直到最近，由于没有已知的小胶质细胞特异性基因编码细胞表面蛋白质，因此很难区分居民小胶质细胞和髓样细胞，这些小胶质细胞和髓样细胞渗透了CNS，因为没有已知的小胶质细胞。这很关键，因为居民小胶质细胞和浸润巨噬细胞具有独立且独特的免疫学功能。我们建议使用最近发现的小胶质细胞的独特分子特征来研究一种转录组 /蛋白质 /生物信息学方法，以研究手术和麻醉后和麻醉后年龄依赖性的小胶质细胞生物学。使用这样的工具，我们发现旧大脑中的小胶质细胞较少，它们表达了较低的免疫相关和稳态基因的水平，并且异氟烷麻醉会影响年轻小鼠的小鼠小鼠的小胶质细胞。基于这些数据，我们提出了旧CNS中的小胶质细胞损耗和失调，负责手术后的认知障碍和手术。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；研究小胶质细胞对使用小胶质细胞消融 /补给的CNS感染和认知障碍的贡献；通过免疫调节小胶质细胞，挽救年龄依赖于年龄的认知脆弱性和麻醉性。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，居民小胶质细胞与浸润性髓样凝胶在手术引起的CNS感染和认知下降中的作用，以及对整个抗小胶质细胞的策略，并定义了固定的小胶质细胞的策略，并如何恢复了cn的策略。老年受试者的认知结果。重要的是，我们还将专门针对小胶质细胞来恢复其稳态分子签名，以减少中枢神经系统感染并改善提出的工作是创新的，因为它使用艺术方法和技术来探索一种新型的小胶质细胞机制，以探索一种术后认知能力下降的新老患者，并且由于临床问题的规模和潜在的方式，因此可以确定新的方法。