Immunometabolic Regulation of MDSCs in Periodontitis

牙周炎中 MDSC 的免疫代谢调节

• 批准号: 10706535
• 负责人: Keith L Kirkwood
• 金额: $ 62.74万
• 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/10706535
• 关键词: 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; Immunophenotyping; Incidence; Inflammation; Inflammation Mediators; Label; Leucocytic infiltrate; Link; Lipopolysaccharides; Macrophage; 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; 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; loss of function; 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.

项目摘要/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和 以破坏牙齿的支撑结构为特征的。尽管有一种明显的关系 肥胖增加和牙周病发病率之间的联系 这两种情况还没有完全理解。慢性低度全身炎症对 肥胖，被称为间质纤维化，是免疫失调的结果，这种失调是由 高血糖状态下细菌脂多糖和饱和游离脂肪酸的持续暴露 条件。众所周知，肥胖会导致未成熟的髓系细胞扩张，这种细胞被称为髓系细胞。 抑制细胞(MDSC)群体，可分化为成熟的破骨细胞，导致牙槽骨 损失。在这个应用中，假设MDSC的扩张和动员有助于肥胖- 通过MDSC代谢重新编程与破骨细胞能力增加相关的牙周炎 导致牙槽骨丢失。本申请中概述的目标将解决以下问题：1) 牙周组织中肥胖诱导的MDSC亚群动员和功能的调控机制 微环境；2)肥胖或非肥胖的HFD如何促进M-MDSC的破骨形成 重新编程的潜力，以及3)肥胖状况是否导致MDSC亚群在 人类牙周病。在这些研究结束时，将提供与 饮食诱导肥胖导致牙周病的细胞机制 多药耐药干细胞在小鼠和人类中的易感性和进展。