Neutrophils and Periodontitis in Diabetes

糖尿病中的中性粒细胞和牙周炎

基本信息

批准号：
7210623
负责人：
THOMAS Elliott VAN DYKE
金额：
$ 34.16万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7210623
关键词：
1,2-diacylglycerol 1-Phosphatidylinositol 3-Kinase 4-ethoxymethylene-2-phenyl-2-oxazoline-5-one Advanced Glycosylation End Products Affect Affinity Alpha Cell Anabolism Anti-Inflammatory Agents Anti-inflammatory Aspirin Binding Biochemical Biochemical Reaction Biochemistry Blood Glucose CREB1 gene Cell membrane Cells Cellular biology Chemicals Chemotactic Factors Complex Complications of Diabetes Mellitus Condition Cytochromes Cytosol Diabetes Mellitus Diglycerides Dinoprostone Dissociation Effectiveness Eicosapentaenoic Acid Enzyme Activation Enzymes Epidemic Exhibits FPR1 gene Fatty Acids Future General Population Glucose Goals HL-60 Cells Hyperglycemia IL8 gene Immune response Immunology In Vitro Individual Infection Inflammatory Response Interleukin-6 Invaded Investigation Leukocytes Leukotriene B4 Lipids Lipoxins MAP Kinase Modules MAPK14 gene Matrix Metalloproteinases Membrane Metalloproteases Methods Modeling Molecular Monomeric GTP-Binding Proteins NADPH Oxidase Nature Oryctolagus cuniculus Oxidases Pathway interactions Patients Periodontal Diseases Periodontitis Peroxides Phosphatidylinositols Phospholipase Phospholipase A2 Phospholipase C Phospholipase D Phosphorylation Play Production Protein Kinase C Rate Research Personnel Risk Role Signal Transduction Pathway Source Superoxides Surface Techniques Tetradecanoylphorbol Acetate Tissues Tumor Necrosis Factor-alpha United States base citrate carrier cytokine diabetic eicosanoid metabolism glycemic control lipid mediator monocyte neutrophil neutrophil cytosol factor 67K pathogen prevent programs receptor receptor for advanced glycation endproducts response sphingosine kinase transcription factor

项目摘要

DESCRIPTION: Diabetes has now reached epidemic status in the United States, affects 6.5% of the general population, and continues to increase at a very alarming rate. Periodontal disease is referred to as the sixth complication of diabetes. There is a reciprocal relationship between diabetes and periodontal disease where each condition exacerbates the other. We have recently observed that neutrophils and monocytes from diabetic patients contain elevated diacylglycerides (DAG), enhanced activity of protein kinase C (PKC), and can release significantly more superoxide and/or tumor necrosis factor-alpha than cells from healthy individuals. Superoxide, cytokines and matrix metalloproteinases play a significant role in the destruction of periodontal tissues in diabetes. Importantly, certain endogenous, anti-inflammatory lipids that result from transcellular metabolism of arachidonic and eicosapentaenoic acid (lipoxins, resolvins) were found to be highly effective in inhibiting superoxide release from diabetic neutrophils and blocking periodontal disease in a rabbit model. In this proposal, we will: 1) determine the molecular mechanisms responsible for alterations in DAG and PKC in diabetic patients; 2) uncover the biochemical basis for priming of neutrophils/monocytes in diabetes, and determine if this priming is prevented when patients are brought under glycemic control and/or treated for periodontal disease; 3) determine the signal transduction pathways by which advanced glycation end products (AGE) prime neutrophils; and 4) determine if certain endogenous anti-inflammatory lipid mediators (e.g., lipoxins, resolvins) can limit the inflammatory response in diabetes by blocking the enhanced functional responses of neutrophils and monocytes from these patients. Techniques of modern biochemistry, immunology and cell biology will be employed in these investigations. These studies have the potential of leading to better methods of treating periodontal disease and perhaps other complications of diabetes.

描述：糖尿病现已在美国达到流行病，影响了普通人群的6.5％，并以非常令人震惊的速度继续增加。牙周疾病被称为糖尿病的第六次并发症。糖尿病与牙周疾病之间存在相互关系，每种病情都会加剧彼此的影响。我们最近观察到，来自糖尿病患者的中性粒细胞和单核细胞含有升高的二酰基甘油酸酯（DAG），蛋白激酶C（PKC）的活性增强，并且比来自健康个体的细胞释放的超氧化物和/或超氧化物和/或肿瘤坏死因子-Alpha。超氧化物，细胞因子和基质金属蛋白酶在糖尿病牙周组织的破坏中起重要作用。重要的是，发现某些是由蛛网膜和eicosapentaenoic酸的跨细胞代谢（Lipoxins，resolvins）引起的某些内源性的，抗炎的脂质，该脂质在抑制糖尿病中性粒细胞中的上氧化含量高效，在兔模型中抑制超氧化物释放。在此提案中，我们将：1）确定糖尿病患者中DAG和PKC改变的分子机制； 2）发现糖尿病中嗜中性粒细胞/单核细胞启动的生化基础，并确定当患者受到血糖控制和/或治疗牙周疾病时是否可以预防这种启动； 3）确定高级糖基化终产物（年龄）中性粒细胞的信号转导途径； 4）确定某些内源性抗炎脂质介质（例如，脂氧蛋白，溶质蛋白）是否通过阻止这些患者的中性粒细胞和单核细胞的功能反应来限制糖尿病的炎症反应。这些研究将采用现代生物化学，免疫学和细胞生物学的技术。这些研究有可能导致更好地治疗牙周疾病以及其他糖尿病并发症的方法。