Neutrophils and Periodontitis in Diabetes

描述：糖尿病现在已经在美国达到流行状态，影响6.5%的总人口，并继续以非常惊人的速度增加。牙周病被称为糖尿病的第六大并发症。糖尿病和牙周病之间有一种相互作用的关系，两种情况都会加剧另一种情况。我们最近观察到，糖尿病患者的中性粒细胞和单核细胞含有较高的二酰甘油酯(DAG)，蛋白激酶C(PKC)活性增强，并能比健康人的细胞释放更多的超氧化物和/或肿瘤坏死因子-α。超氧化物歧化酶、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，花生四烯酸和二十碳五烯酸跨细胞代谢产生的某些内源性抗炎脂(脂氧素、分解素)被发现在抑制糖尿病中性粒细胞释放超氧化物和阻断兔牙周疾病方面非常有效。 在这项建议中，我们将：1)确定导致糖尿病患者DAG和PKC变化的分子机制；2)揭示糖尿病患者中性粒细胞/单核细胞启动的生化基础，并确定当患者接受血糖控制和/或牙周疾病治疗时，是否阻止这种启动；3)确定晚期糖基化终产物(AGE)启动中性粒细胞的信号转导途径；以及4)确定某些内源性抗炎脂质介质(如脂联素、溶血素)是否通过阻断这些患者中性粒细胞和单核细胞增强的功能反应来限制糖尿病的炎症反应。这些研究将运用现代生物化学、免疫学和细胞生物学的技术。这些研究有可能导致更好的方法来治疗牙周病，也许还有其他糖尿病并发症。

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.