Pathogen-Induced Inflammation in Platelet Function

虽然有证据表明慢性炎症和感染促进了斑块的形成，但急性 感染与短暂的冠状动脉和血管不稳定风险增加五倍有关 由血小板依赖性血栓形成引起的综合征。虽然许多细菌株能诱导血小板 细菌刺激血小板的机制--聚集--研究得很少。在……里面 利用全面的微阵列分析的初步数据，以及几乎 2,000名受试者中，我们发现了心血管疾病患者血小板基因表达的不同模式 疾病。在血小板中检测到几种TLR，尤其是TLR2和IL1R的表达 在患有心血管疾病的患者中增加。重要的是，TLR在血小板中的功能 建立为血小板与TLR2配体的孵育呈剂量依赖性地诱导血小板激活 和聚合。此外，我们还发现了增强的血小板功能和血小板-单核细胞/中性粒细胞 与肺炎链球菌体内感染结合，与牙龈假单胞菌孵化。的核心假说 总体规划项目是“通过先天免疫识别调节病原体刺激 炎症介质调节宿主免疫细胞功能，导致慢性炎症性疾病“。 项目1的中心假设是细菌介导了血栓形成和炎症过程。 为了研究这一假设，我们提出了以下目标： 目的1.明确TLR2和IL-1R在肺炎衣原体和牙龈假单胞菌促进血小板功能中的作用。 功能。 目的2.明确肺炎衣原体和牙龈假单胞菌对依赖TLR2和IL1R的血小板信号通路和巨核细胞依赖的NFkappaB转录的调节作用。 目的3.明确TLR2和IL-1R在肺炎衣原体和肺炎衣原体诱导的血小板特异性反应中的作用。 活体牙龈依赖性血栓形成。

While there is evidence that chronic inflammation and infection promotes plaque formation, acute infections are associated with a transient five-fold increased risk of unstable coronary and vascular syndromes caused by platelet dependent thrombosis. While many strains of bacteria induce platelet aggregation, the mechanisms by which bacteria stimulate platelets has had minimal investigation. In preliminary data utilizing comprehensive microarray analyses, and a large community cohort of almost 2,000 subjects, we found distinct patterns of platelet gene expression in patients with cardiovascular disease. While several TLRs were detected in platelets, the expression of TLR2 and IL1R in particular were increased in patients with cardiovascular disease. Importantly, the functionality of TLR in platelets was established as incubation of platelets with TLR2 ligands dose-dependently induced platelet activation and aggregation. In addition, we found enhanced platelet function and platelet-monocyte/neutrophil binding with C. pneumoniae infection in vivo, and P. gingivalis incubation. The central hypothesis of the overall program project is that "Pathogen stimulation via innate immune recognition modulates inflammatory mediator regulation of host immune cell function resulting in chronic inflammatory disorders". The central hypothesis of Project 1 is that bacteria mediate pro-thrombotic and -inflammatory processes in platelets via innate immune pathways. To investigate this hypothesis, we propose the following Aims: Aim 1. To define the role of TLR2 and IL-1R in C. pneumoniae and P. gingivalis enhanced platelet function. Aim 2. To define C. pneumoniae and P. gingivalis mediated modulation of TLR2- and IL1R-dependent signaling pathways in platelets and NFkappaB-dependent transcription in megakaryocytes. Aim 3. To define the role of TLR2 and IL-1 R in platelet specific responses to C. pneumoniae and P. gingivalis dependent thrombosis in vivo.