Neutrophils and Periodontitis in Diabetes

产品说明：糖尿病在美国已经达到流行病的状态，影响6.5%的普通人群，并继续以非常惊人的速度增长。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存在相互关系，每种情况都会加重另一种情况。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酯（DAG），增强的蛋白激酶C（PKC）活性，并且可以比来自健康个体的细胞释放显著更多的超氧化物和/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，发现由花生四烯酸和二十碳五烯酸的跨细胞代谢产生的某些内源性抗炎脂质（脂氧素、消退素）在抑制糖尿病中性粒细胞释放超氧化物和阻断兔模型中的牙周病方面非常有效。 在本提案中，我们将：1）确定糖尿病患者中DAG和PKC改变的分子机制; 2）揭示糖尿病中性粒细胞/单核细胞启动的生化基础，并确定当患者处于血糖控制和/或治疗牙周病时，这种启动是否被阻止; 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;和4）确定某些内源性抗炎脂质介质（例如，脂氧素、消退素）可以通过阻断来自这些患者的嗜中性粒细胞和单核细胞的增强的功能反应来限制糖尿病中的炎症反应。现代生物化学、免疫学和细胞生物学技术将用于这些研究。这些研究有可能导致更好的方法来治疗牙周病和糖尿病的其他并发症。

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.