Thrombosis Propensity Determinants of Inflammation

炎症的血栓形成倾向决定因素

• 批准号: 7115397
• 负责人: WHYTE G OWEN
• 金额: $ 28.81万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-24 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7115397
• 关键词: bacterial disease; clinical research; cytokine; disease /disorder proneness /risk; endotoxins; genetically modified animals; gram negative bacteria; host organism interaction; human subject; immunotherapy; inflammation; laboratory mouse; lipopolysaccharides; periodontium disorder; platelet aggregation; platelets; thrombosis; toll like receptor

DESCRIPTION (provided by applicant): The goal of the proposal is understanding the link between inflammation associated with low-grade bacterial infections and thrombotic processes. The underlying hypothesis is that acute or chronic low-grade infection primes platelets and thrombin-generating pathways to increase propensity for thrombosis. The hypothesis will be approached by measuring responses, in vivo and in vitro, of platelets, the clotting system and the vascular anticoagulant system, to acute and chronic doses of endotoxin from Gram-negative bacteria. The studies will take advantage of mice with genetic deficiency in the phylogenetically conserved receptor (toll-like-receptor-4) required for initiating innate immunity to endotoxin of Gram-negative bacteria. Measurements will include intravascular thrombin generation and inhibition and platelet microaggregation in vivo. In addition a family of in vitro assays of platelet physiology and pharmacology, leukocyte interactions and thrombin generation in blood in conjunction with measurement of inflammatory cytokines will provide information about changes in threshold, gain and amplitude of thrombogenic responses. The unique aspect of this proposal is the ability to distinguish acute, non-genomic actions of endotoxin on platelets through the innate immune response, from longer term consequences of changes in gene transcription. Effects of chronic low grade bacterial infection will be studied in humans undergoing initial therapy for advanced bacterial periodontal disease. Blood samples will be obtained from these patients before and after successful treatment, which does not involve pharmacotherapy. These blood samples will be assayed in parallel with those from the mice. This application is highly responsive to the RFA, because it focuses on translational research at the interface of thrombosis and inflammation. The toll family receptors of innate immunity are well characterized for defense against bacteria. We will extend this characterization by defining the mechanism by which these receptors influence thrombotic propensity.

描述（由申请人提供）： 该提案的目的是了解与低级细菌感染与血栓形成过程相关的炎症之间的联系。潜在的假设是急性或慢性低级感染素质血小板和凝血酶生成的途径增加血栓形成倾向。该假设将通过测量血小板，凝血系统和血管抗凝剂系统的反应，从革兰氏阴性细菌中测量血小板，凝血系统和血管抗凝剂系统的反应。研究将利用具有遗传缺乏症的小鼠在系统发育受体（TOLL-LIKE-TORPEPTOR-4）中启动先天免疫对革兰氏阴性细菌的内毒素所需的小鼠。测量值将包括血管内凝血酶产生和抑制作用以及体内血小板微聚集。此外，血小板生理学和药理学的体外测定系列，血清细胞相互作用和血液中血液蛋白的产生以及炎症细胞因子的测量将提供有关阈值，增益和振幅血栓形成反应的变化的信息。该提案的独特方面是，通过天生的免疫反应从基因转录的长期后果来区分内毒素在血小板上的急性非基因组作用的能力。将在接受晚期细菌牙周疾病的初始治疗中研究慢性低级细菌感染的影响。成功治疗前后，将从这些患者那里获得血液样本，这不涉及药物治疗。这些血液样本将与小鼠同行分析。该应用对RFA的反应很高，因为它专注于血栓形成和炎症界面的翻译研究。先天免疫的收费家族受体的特征是防御细菌。我们将通过定义这些受体影响血小板倾向的机制来扩展这种表征。