Immunometabolic Regulation of MDSCs in Periodontitis

牙周炎中 MDSC 的免疫代谢调节

• 批准号: 10560308
• 负责人: Keith L Kirkwood
• 金额: $ 67.78万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560308
• 关键词: Address; Adult; Affect; Alveolar Bone Loss; Architecture; Cardiovascular Diseases; Cells; Chronic; Complex; Diabetes Mellitus; Diet; Disease; Disease Progression; Disease susceptibility; Enzymes; Exposure to; Flow Cytometry; Functional disorder; Funding Opportunities; Future; Genetic; Gingiva; Health; Human; Hyperglycemia; Immune; Immune system; Incidence; Infiltration; Inflammation; Inflammation Mediators; Label; Leukocytes; Link; Lipopolysaccharides; Memory; Metabolic; Metabolic Diseases; Metabolism; Molecular; Mucosal Immunity; Mus; Myeloid Cells; Myeloid-derived suppressor cells; Nonesterified Fatty Acids; Obesity; Oral; Oral cavity; Osteoclasts; Patients; Periodontal Diseases; Periodontal Infection; Periodontitis; Periodontium; Phenotype; Play; Population; Process; Production; Quality of life; Recruitment Activity; Regulation; Risk Factors; Role; Severities; Site; Therapeutic; Thinness; Tissues; Training; adipokines; alveolar bone; alveolar destruction; bone; bone loss; bone quality; chronic inflammatory disease; cohort; comorbidity; cytokine; diet-induced obesity; dietary; gain of function; immune function; in vivo imaging; insight; macrophage; microbial colonization; monocyte; obese patients; obesity development; osteoclastogenesis; osteoimmunology; peripheral blood; recruit; response; systemic inflammatory response; transcriptome sequencing; transcriptomics

PROJECT SUMMARY/ABSTRACT Periodontitis is a common chronic inflammatory disease affecting over half of the US adult population and characterized by destruction of the supporting structures of the teeth. Although there is a clear relationship between increased obesity and periodontal disease incidence, the mechanisms that underpin the links between these two conditions are not completely understood. Chronic low-grade systemic inflammation in response to obesity, referred to as metainflammation, is a consequence of immune dysregulation that results from the continuous exposure to bacterial lipopolysaccharide and saturated free fatty acids under hyperglycemic conditions. Obesity is known to cause the expansion of immature myeloid cells, termed myeloid-derived suppressor cell (MDSC) populations, which can differentiate into mature osteoclasts, resulting in alveolar bone loss. In this application, it is hypothesized that MDSC expansion and mobilization contribute towards obesity- associated periodontitis through MDSC metabolic reprograming with increased osteoclastic capacity contributing towards alveolar bone loss. The aims outlined in this application will address questions to determine: 1) the mechanisms that govern obesity-directed MDSC subpopulation mobilization and function in the periodontal microenvironment; 2) how obesity or HFD, independent of obesity, contributes toward M-MDSC osteoclastogenic reprogramming potential, and 3) if obesity status contributes towards differences in MDSC subpopulations in human periodontal disease. At the conclusion of these studies, new evidence will be provided related to the cellular mechanisms engaged during diet-induced obesity that contribute towards periodontal disease susceptibility and progression through MDSC populations in mice and humans.

项目概要/摘要 牙周炎是一种常见的慢性炎症性疾病，影响超过一半的美国成年人口 其特征是牙齿的支撑结构被破坏。虽然有明确的关系 肥胖与牙周病发病率增加之间的联系机制 这两个条件尚未完全理解。慢性低度全身炎症反应 肥胖，被称为元炎症，是免疫失调的结果，而免疫失调是由 高血糖下持续暴露于细菌脂多糖和饱和游离脂肪酸 状况。已知肥胖会导致未成熟骨髓细胞的扩增，称为骨髓源性细胞。 抑制细胞（MDSC）群体，可以分化为成熟的破骨细胞，从而形成牙槽骨 损失。在此应用中，假设 MDSC 扩张和动员有助于肥胖 - 通过 MDSC 代谢重编程与破骨细胞能力增加相关的牙周炎 导致牙槽骨流失。本申请概述的目标将解决确定以下问题：1) 控制牙周中肥胖导向的 MDSC 亚群动员和功能的机制 微环境； 2) 独立于肥胖的肥胖或 HFD 如何促进 M-MDSC 破骨细胞生成 重编程潜力，以及 3) 肥胖状态是否会导致 MDSC 亚群的差异 人类牙周病。在这些研究结束时，将提供与以下方面相关的新证据： 饮食引起的肥胖导致牙周病的细胞机制 小鼠和人类 MDSC 群体的易感性和进展。