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Targeting Succinate Signaling Impedes Periodontitis Progression

靶向琥珀酸信号传导阻止牙周炎进展

基本信息

批准号：
9882976
负责人：
DANA T GRAVES
金额：
$ 44.48万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9882976
关键词：
Alveolar Bone Loss Anaerobic Bacteria B-Lymphocytes Bacteria Biological Response Modifiers Bone Resorption Contralateral Data Dendritic Cells Diabetes Mellitus Diabetic mouse Diet Disease Progression Enzyme-Linked Immunosorbent Assay Flow Cytometry Germ-Free Gingival Crevicular Fluid Growth High Fat Diet Histologic Histology Homeostasis Hyperglycemia Hyperglycemic Mice Immunofluorescence Immunologic Immunohistochemistry In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injections International Knock-out Knockout Mice Leukocytes Measures Metabolic Metabolic Diseases Mus Non-Insulin-Dependent Diabetes Mellitus Oral Osteoclasts Pathogenesis Pathogenicity Patients Periodontal Diseases Periodontitis Periodontium Receptor Signaling Reporting Risk Factors Role Side Signal Transduction Site Stimulus Succinates T-Lymphocyte TNFSF11 gene Testing Tissues Topical application Tumor-infiltrating immune cells Type 2 diabetic Wild Type Mouse adaptive immune response alveolar bone bone loss cytokine diabetic diabetic patient efficacy testing feeding gut microbiome histological specimens immunogenic immunosuppressive macrophages in vivo metagenomic sequencing microCT microbial mouse model neutrophil novel oral microbial community oral microbiome osteoclastogenesis periodontopathogen precursor cell prevent protective effect receptor response transcriptome transcriptome sequencing

项目摘要

Abstract Type 2 Diabetes is recognized as an important risk factor for more severe and progressive periodontitis. Diabetic condition may accelerate periodontitis through metabolic dysregulation, shift in bacterial colonization, inflammation, and bone loss. We recently found that succinate activates succinate receptor (SucnR1) to stimulate osteoclastogenesis and bone resorption. Our preliminary data further show (1) succinate was elevated in the gingival crevicular fluid (GCF) from periodontitis patients and the elevation was significantly greater in patients with both periodontitis and T2D; (2) spontaneous periodontitis in T2D mice was accompanied by elevated succinate levels in the periodontium and altered gastrointestinal microbiome compare to normal mice; (3) succinate favors the growth of periodontal pathogens in vitro; (4) exogenous succinate enhances periodontal bone loss in wild type (WT); and (5) the periodontal bone loss is mitigated in SucnR1 knock out mice (KO) mice. The current proposal is built on strong preliminary data to determine whether succinate elevation accelerates periodontal disease progression. We will employ mouse models to test our hypotheses that targeting succinate signaling prevents accelerated periodontal disease pathogenesis. In Aim 1 we will use mice fed on normal diet, mice fed on High Fat Diet (HFD) which become hyperglycemic, and succinate receptor knock out mice (SucnR1_KO) to determine whether succinate/SucnR1 signaling influences systemic response and alters oral microbiota in normal and hyperglycemia conditions. We will use bacterial transfer from the periodontal site to germ free mice to test the pathogenicity as measured by bacteria-induced bone loss. Our working hypothesis is bacteria from HFD diabetic mice will induce more bone loss than bacteria from matched normoglycemic controls. In Aim 2 we will determine whether succinate activates SucnR1 to enhance periodontal bone loss stimulated by inflammation stimulus. In Aim 3 we will determine whether blocking succinate signaling in pre-osteoclasts alleviates periodontium bone loss. We will use lysMCre, SucnR1L/L mouse model to assess whether succinate signaling through its receptor to enhance non-inflammatory stimuli induced bone loss. We will also test the efficacy of a specific SucnR1 antagonist in preventing periodontitis in a T2D mouse model that spontaneously develop periodontitis. We propose that via activation of SucnR1, succinate has significant implications in periodontal disease and by delineating this novel mechanism, we will help to prevent periodontal bone loss in diabetic patients.

摘要