Diabetes-enhanced Experimental Periodontitis

糖尿病增强的实验性牙周炎

• 批准号: 10375888
• 负责人: DANA T GRAVES
• 金额: $ 43.75万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375888
• 关键词: Affect; Animals; Apical; Area; Bacteria; Bacterial Infections; Behavior; Bioinformatics; Bone Resorption; Candidate Disease Gene; Cell Communication; Cell physiology; Cells; Connective Tissue; Coupled; Data; Data Set; Dendritic Cells; Diabetes Mellitus; Disease; Disease Progression; Disease susceptibility; Epithelial; Event; Frequencies; Gene Expression; Gene Expression Profile; Genes; Gingiva; Human; Immune response; Immunofluorescence Immunologic; In Vitro; Inflammatory; Leukocytes; Location; Methods; Mus; Osteogenesis; Pattern; Periodontal Diseases; Periodontitis; Periodontium; Phenotype; Predisposition; Regulatory T-Lymphocyte; Risk; Role; Severities; Spatial Distribution; Specimen; T-Lymphocyte; Techniques; Testing; Therapeutic; Therapeutic Intervention; Tissues; adaptive immune response; base; bone; cell type; diabetic; dysbiosis; experimental study; follow-up; functional outcomes; improved outcome; in vivo; inhibitor; insight; microbial; mouse model; novel; oral cavity epithelium; pre-clinical; recruit; response; single-cell RNA sequencing; small molecule; tool; transcriptomics; translational study

Abstract: Diabetes increases the risk and frequency of bacterial infection and alters the adaptive immune response. Surprisingly little is known about the impact of diabetes on dendritic cells and how it may increase susceptibility to periodontitis. The lack of understanding until recently has been hampered by limited technical ability to define the specific behavior of dendritic cells and interactions with other cell types during active periodontal disease. New advances in single cell transcriptomics such as single cell RNA-seq (scRNA-seq) have provided an exponential increase in our ability to dissect the behavior of specific cell types under various disease conditions. The studies proposed will elucidate how diabetes alters dendritic cell function in a way that contributes to periodontitis. New Prel Data has been added resulting a completely revised proposal demonstrating that diabetes alters dendritic cell gene expression in vivo as assessed by scRNA-seq. The studies proposed involve sophisticated bioinformatic analysis of scRNA-seq data very recently obtained and a new experimental approach, spatially resolved transcriptomics, to provide new insight on how diabetes may affect dendritic cell activity. The risk in this approach in Aim 1 is mitigated by Prel Data that have identified potential key genes that are up- or down-regulated in the periodontium in dendritic cells during active periodontal disease progression, which will be further investigated by bioinformatic analysis of scRNA-seq results. In addition, translational studies are proposed in Aim 1 as a preclinical step for therapeutic intervention. Functional studies are proposed in Aim 2 to examine gene candidates in vitro to establish cause and effect relationships between candidate genes and functional outcomes. Experiments in Aim 3 will use spatial transcriptomics to define how diabetes may alter the spatial compartments in which DC and other leukocytes are found during the initiation of periodontitis and investigate co-localization of cells and pattern of inflammatory gene expression to better understand their interaction. Taken together this proposal combines an unbiased approach for hypothesis discovery with functional in vitro and in vivo methods for hypothesis testing and establishing mechanisms.

摘要：糖尿病增加细菌感染的风险和频率，改变获得性免疫。 回应。令人惊讶的是，人们对糖尿病对树突状细胞的影响以及它如何增加知之甚少。 易患牙周炎。直到最近，缺乏理解一直受到有限的技术支持的阻碍 能够定义树突状细胞的特定行为以及在活动期间与其他类型细胞的相互作用 牙周病。单细胞转录组学的新进展，如单细胞rna-seq(scrna-seq) 使我们分析特定细胞类型在各种疾病下的行为的能力呈指数级增长 条件。提出的研究将阐明糖尿病如何改变树突状细胞的功能 会导致牙周炎。添加了新的PREL数据，从而产生了完全修订的提案 表明糖尿病改变了体内树突状细胞基因的表达，通过scRNA-seq评估。这些研究 建议涉及对最近获得的scRNA-seq数据进行复杂的生物信息学分析，并提出了一种新的 实验方法，空间分辨转录组学，为糖尿病可能的影响提供新的见解 树突状细胞活性。目标1中这种方法中的风险通过已识别出潜力的PREL数据来减轻 活动性牙周病中树突状细胞在牙周组织中上调或下调的关键基因 这将通过对scRNA-seq结果的生物信息学分析来进一步研究。此外, 翻译研究是在目标1中提出的，作为治疗干预的临床前步骤。功能研究 在目标2中建议在体外检查候选基因，以建立 候选基因和功能结果。Aim 3的实验将使用空间转录来定义 糖尿病可能会改变DC和其他白细胞在发病过程中所处的空间间隔 牙周炎，并研究细胞共定位和炎症基因表达的模式，以更好地 了解他们的互动。综上所述，这一建议结合了一种公正的假设方法 用体外和体内功能方法进行假说检验和建立机制的发现。