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Immunometabolic Regulation of MDSCs in Periodontitis

牙周炎中 MDSC 的免疫代谢调节

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/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，以牙齿的支撑结构的破坏为特征。虽然有明显的关系肥胖和牙周病发病率增加之间的联系，这两个条件还没有完全理解。慢性低度全身性炎症反应肥胖症，被称为后炎症，是免疫失调的结果，高血糖状态下持续暴露于细菌脂多糖和饱和游离脂肪酸条件已知肥胖会导致未成熟的髓样细胞扩增，称为髓源性抑制细胞（MDSC）群体，可以分化成成熟的破骨细胞，导致牙槽骨损失在本申请中，假设MDSC扩增和动员有助于肥胖。相关牙周炎通过MDSC代谢重编程与骨吸收能力增加，导致牙槽骨流失在本申请中概述的目标将解决问题，以确定：1）控制肥胖相关MDSC亚群动员和牙周功能的机制微环境; 2）肥胖或HFD，独立于肥胖，如何有助于M-MDSC破骨细胞生成重编程潜力，以及3）如果肥胖状态导致MDSC亚群的差异，人类牙周病在这些研究结束时，将提供与饮食诱导的肥胖导致牙周病的细胞机制在小鼠和人类中通过MDSC群体的易感性和进展。