In vivo study of diabetic hyperglycemia and inflammation

糖尿病高血糖和炎症的体内研究

基本信息

批准号：
7118780
负责人：
ROBERT GYURKO
金额：
$ 26.22万
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：
2005-09-01 至 2010-07-31
项目状态：
已结题

项目摘要

DESCRIPTION: Diabetes increases the susceptibility to infectious diseases, including periodontal disease. Periodontal disease is initiated by bacteria, but components of the host immune response are thought to contribute significantly to periodontal tissue damage. Of particular interest, free radicals such as superoxide play a prominent role both in diabetic complications and in periodontal tissue damage. Free radicals are produced in large quantities by polymorphonuclear (PMN) leukocytes, and abnormal PMN function is detected both in diabetes and in periodontal disease. This proposal is intended to help elucidate the molecular mechanisms that link diabetes and periodontal disease. The chief hypothesis to be tested is that elevated blood glucose activates PMN leukocytes, which in turn release excess superoxide causing tissue damage in the periodontium and in other tissues. A second focal point of these experiments is the evaluation of novel endogenous anti-inflammatory lipids, such as lipoxins, resolvins and docosatrienes. These molecules are formed locally during inflammation, and they antagonize the effect of PMN leukocytes and promote resolution of inflammation. Experiments are designed to test the effectiveness of stable analogs of lipoxins, defensins and docosatrienes in decreasing inflammatory tissue damage in diabetes and periodontal disease. These experiments employ a novel animal model of insulin-dependent diabetes, the Akita mice, and another mouse line, the Ncfl mice, whose PMN are deficient in superoxide generation. Akita and Ncf1 mice will be crossed to generate a double mutant experimental model in which the contribution of superoxide to diabetic tissue damage can be analyzed in alveolar bone and in soft tissue. The findings from these experiments might be important not only from the view of periodontal health, but also for diabetes research. Moreover, findings on novel lipid inhibitors of inflammation will be important in evaluating the therapeutic potential of these compounds in resolving inflammation in periodontal and other inflammations.

描述：糖尿病会增加对传染病（包括牙周病）的易感性。牙周病是由细菌引发的，但宿主免疫反应的成分被认为对牙周组织损伤有显着影响。特别令人感兴趣的是，超氧化物等自由基在糖尿病并发症和牙周组织损伤中发挥着重要作用。多形核 (PMN) 白细胞大量产生自由基，在糖尿病和牙周病中均检测到异常的 PMN 功能。该提案旨在帮助阐明糖尿病和牙周病之间的分子机制。要测试的主要假设是，血糖升高会激活中性粒细胞（PMN）白细胞，进而释放过量的超氧化物，导致牙周组织和其他组织损伤。这些实验的第二个焦点是评估新型内源性抗炎脂质，例如脂氧素、分解素和二十二碳三烯。这些分子是在炎症过程中局部形成的，它们拮抗中性粒细胞白细胞的作用，促进炎症的消退。实验旨在测试脂氧素、防御素和二十二碳三烯的稳定类似物在减少糖尿病和牙周病炎症组织损伤方面的有效性。这些实验采用了一种新型的胰岛素依赖性糖尿病动物模型——秋田小鼠，以及另一种小鼠品系——Ncfl小鼠，它们的中性粒细胞缺乏超氧化物的生成。 Akita 和 Ncf1 小鼠将杂交产生双突变实验模型，在该模型中可以分析牙槽骨和软组织中超氧化物对糖尿病组织损伤的贡献。这些实验的结果不仅从牙周健康的角度来看很重要，而且对于糖尿病研究也很重要。此外，新型脂质炎症抑制剂的发现对于评估这些化合物在解决牙周炎症和其他炎症方面的治疗潜力非常重要。