Impact of acid ceramidase activity on MIF-mediated migration of circulating osteoclast precursors to periodontal bone lesions in relation to aging

酸性神经酰胺酶活性对 MIF 介导的循环破骨细胞前体向与衰老相关的牙周骨病变迁移的影响

• 批准号: 10286664
• 负责人: Alexandru Movila
• 金额: $ 38万
• 依托单位: NOVA SOUTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10286664
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid beta-Protein; Attenuated; Autopsy; Blood Circulation; Brain; Cathepsins B; Cell Membrane Permeability; Cells; Ceramides; Data; Development; Experimental Models; Female; Foundations; Human; Immune response; Impaired cognition; In Vitro; Inflammation; Inflammatory; Knock-out; Late Onset Alzheimer Disease; Lesion; Ligation; Lipids; Lipopolysaccharides; Macrophage Activation; Mediating; Memory; Microglia; Molecular; Mus; Nerve Degeneration; Neuraxis; Osteoclasts; Pathogenicity; Pathology; Patients; Peptide Hydrolases; Peptide Initiation Factors; Periodontitis; Pilot Projects; Porphyromonas gingivalis; Reporting; Research Project Grants; Risk Factors; Role; TLR2 gene; Technology; Time; Virulence Factors; Wild Type Mouse; age related; base; bone; carboxypeptidase C; dihydroceramide; galactosylgalactosylglucosylceramidase; hyperphosphorylated tau; macrophage; male; migration; mouse model; multidisciplinary; neuroinflammation; novel; novel therapeutic intervention; parent grant; periodontopathogen; prevent; sex; single-cell RNA sequencing; skills; transcriptome

ABSTRACT This application will investigate the novel pathogenic host-bacterial interactions of which microglial-associated neuroinflammatory hallmarks of Late Onset Alzheimer’s disease (LOAD) emerges with periodontitis in relation to aging. The emerging evidence indicates that ligation of lipopolysaccharide (LPS) produced by the key periodontal pathogen Porphyromonas gingivalis, with Toll-Like Receptors-2 and -4 may serve as a risk factor for the initiation and/or progression of LOAD induced in young wild type mice. However, using the active R01 parent grant, we recently demonstrated that P. gingivalis-LPS/TLRs axis is attenuated in relation to aging, suggesting that an alternative pro-inflammatory mechanism may be engaged in the age-dependent pathologies, including LOAD. Our group also found that P. gingivalis produces a novel class of a host cell-membrane permeable ceramide lipid termed phosphoglycerol dihydroceramide (PGDHC) which elevates macrophage activation independently of TLRs. Furthermore, a study demonstrated that among the virulence factors produced by P. gingivalis, only PGDHC is found abundantly in the periodontal lesions as well as in the blood circulation. In addition, our preliminary data show that PGDHC is frequentely detected in the postmortem brains of patients with Alzheimer’s disease compared to that in healthy indviduals. Other preliminary results demonstrated that PGDHC elevates periodontal inflammation by acting on lysosomal protease Cathepsin B. Furthermore, it was reported that cathepsin B exacerbated the LOAD-like neuroinflammation and neurodegeneration in a mouse model of periodontitis induced by P. gingivalis. Although studies of Alzheimer’s disease pathology have predominantly focused on the amyloid-β and hyperphosphorylated tau, recent multidisciplinary findings strongly suggest that neuroinflammation associated with aberrant immune responses of the central nervous system (CNS) resident macrophages, microglia, is the third hallmark features of LOAD. However, it remains elusive whether PGDHC can promote microglia activation leading to the LOAD neuroinflammation. Based on these lines of evidence, we hypothesize that, in the context of LOAD-associated neuroinflammation, a novel PGDHC/Cathepsin B axis is engaged in the microglial activation. In the course of this one-year pilot study, we will investigate the impact of PGDHC on the cathepsin B-dependent activation of mouse primary microglia cells in vitro as well as the LOAD-like neuroinflammation and memory skills in relation to aging using female and male Cathepsin B-knock out and their wild type mice. Then, we will employ the single cell RNA-seq technology to identify transcriptome profiles between distinct subtypes of microglia isolated from the brains of wild type mice in relation to aging and sex. The proposed research project will, for the first time, establish the possible role of P. gingivalis-derived dihydroceramides in neuroinflammation and will provide a foundation for the development of a novel therapeutic approach for preventing periodontitis-associated cognitive decline in LOAD.

抽象的 该应用将研究与小胶质细胞相关的新型致病宿主 - 细菌相互作用 晚期发病阿尔茨海默氏病（负载）的神经炎症标志与牙周炎有关 衰老。新兴的证据表明，密钥产生的脂多糖（LPS）的连接 牙周病原体卟啉单胞菌，具有Toll样受体-2和-4可能是危险因素 年轻的野生型小鼠诱导的负载的主动性和/或进展。但是，使用活动R01父 格兰特（Grant），我们最近证明了牙龈疟原虫-lps/tlrs轴相对于衰老而减弱，这表明 替代性促炎机制可能会参与年龄依赖的病理，包括 加载。我们的小组还发现，牙龈疟原虫会产生一类新型的宿主细胞透（可渗透宿主细胞） 神经酰胺脂质称为磷酸甘油二氢可酰胺（PGDHC），该脂肪酰胺（PGDHC）提高了巨噬细胞的活化 独立于TLR。此外，一项研究表明，在P.产生的病毒因子中 牙龈，仅在牙周病变以及血液循环中绝对发现PGDHC。 此外，我们的初步数据表明，患者的死后大脑经常检测到PGDHC 与健康的异性恋者相比，阿尔茨海默氏病。其他初步结果表明 PGD​​HC通过作用于溶酶体蛋白酶组织蛋白酶B升高牙周炎症。此外，它是 报道组织蛋白酶B加剧了小鼠中的载荷样神经炎症和神经变性 尽管对阿尔茨海默氏病病理学的研究具有 主要集中于淀粉样蛋白β和高磷酸化的tau，最近的多学科发现很强 表明与中枢神经系统异常免疫反应相关的神经炎症 （CNS）居民巨噬细胞小胶质细胞是负载的第三个标志特征。但是，它仍然难以捉摸 PGD​​HC是否可以促进小胶质细胞活化，从而导致负载神经炎症。基于这些线 在证据中，我们假设，在与负载相关的神经炎症的背景下，一种新型 PGD​​HC/组织蛋白酶B轴进行小胶质细胞激活。在这项为期一年的试点研究的过程中，我们 将研究PGDHC对小鼠原代小胶质细胞的组织蛋白酶B依赖性激活的影响 在体外以及与衰老有关的男性和雄性的类似负载的神经炎症和记忆技巧 组织蛋白酶B旋转及其野生型小鼠。然后，我们将使用单个单元RNA-seq技术来 识别从野生型小鼠大脑中分离的小胶质细胞的不同亚型之间的转录组轮廓 与衰老和性别有关。拟议的研究项目将首次确定 牙龈疟原虫衍生的神经炎症中的二氢可酰胺，将为开发提供基础 一种新型的热方法，用于预防牙周炎相关的负载认知下降。