Novel Lipid Mediators in LAP and Resolution

LAP 和分辨率中的新型脂质介质

• 批准号: 6882260
• 负责人: THOMAS Elliott VAN DYKE
• 金额: $ 23.71万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6882260
• 关键词: RNA splicing; chemical structure function; diacylglycerols; enzyme activity; gene mutation; genetic promoter element; genetic regulation; human subject; inflammation; isozymes; laboratory rabbit; lipids; molecular biology; molecular pathology; neutrophil; pathologic process; patient oriented research; periodontitis; pharmacology; phosphotransferases; protein kinase C; protein quantitation /detection; second messengers; superoxides

The goal of this proposal is to determine the exact roles of certain lipid second messenger molecules [i.e., diacylglycerols (DAG's)] and endogenous mediators [resolvins, docosatrienes (DT), lipoxins] in periodontal inflammation, and to continue to develop novel molecular strategies to pharmacologically interrupt the inflammatory cascade. We will focus on Localized Aggressive Periodontitis (LAP, formerly known as localized juvenile periodontitis, LJP), which presents neutrophils with a classically "primed" phenotype, i.e. hyper-responsiveness in superoxide production during cell stimulation. Neutrophils (PMN) isolated from peripheral blood of LAP patients exhibit a three fold elevation in cellular diacylglycerol and a two to three fold increase in membrane associated protein kinase (PKC) activity. A marked decrease in the alpha-isoform of DAG kinase (DGKalpha) activity occurs in these cells, which is likely to be responsible for the elevated levels of DAG and the priming phenomena. Work by our group (see Project 0001) has revealed new classes endogenous lipid mediators (LM), the resolvins and docosatrienes (DT), which are potent natural inhibitors of inflammation in a wide variety of animal models including the rabbit model of periodontal destruction. These compounds block superoxide production and chemotaxis in stimulated PMN with certain agonists. To accomplish our goals, we will evaluate the molecular mechanisms responsible for the dramatic decrease in DGKalpha activity in LAP PMN at the genetic and biochemical level, identify the isoforms of membrane-bound PKC that are elevated in LAP PMN due to increased DAG, and determine how these elevations in DAG/membrane bound PKC "prime" the NADPH-oxidase complex to produce more superoxide/peroxide in LAP PMN. Finally, we will evaluate the beneficial effect of resolvins and docosatrienes on periodontal inflammation in situ and compare our results to those observed for lipoxins and their stable analogs. Techniques of molecular biology, biochemistry, and animal pathophysiology will be used in these studies.

本提案的目标是确定某些脂质第二信使分子[即二酰基甘油（DAG's）]和内源性介质[resolvins， docosatrienes (DT)， lipoxins]在牙周炎症中的确切作用，并继续开发新的分子策略来从药理学上中断炎症级联反应。我们将重点关注局部侵袭性牙周炎（LAP，以前称为局部青少年牙周炎，LJP），它表现为中性粒细胞具有经典的“启动”表型，即在细胞刺激过程中超氧化物产生的高反应性。从LAP患者外周血中分离的中性粒细胞（PMN）表现出细胞二酰基甘油的三倍升高和膜相关蛋白激酶（PKC）活性的两到三倍增加。α -异构体的显著减少