Cardiac Depression in Gram-Positive Sepsis--Role of TLR2

革兰氏阳性脓毒症中的心脏抑制——TLR2 的作用

• 批准号: 6770996
• 负责人: JESUS G VALLEJO
• 金额: $ 23.18万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-02 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6770996
• 关键词: Staphylococcus aureus; bacteria infection mechanism; bacterial disease; biological signal transduction; blood toxicology; cytoskeletal proteins; glycoproteins; gram positive bacteria; heart contraction; heart disorder; heart ventricle; immunotherapy; inflammation; interleukin 1; interleukin 6; laboratory mouse; membrane proteins; molecular pathology; myocardium disorder; nitric oxide synthase; protein structure function; receptor; septic shock; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): The systemic inflammatory response induced by gram-positive bacteria is associated with considerable morbidity and mortality attributable to refractory hypotension, cardiac dysfunction and multiorgan failure. Despite the potentially important role that TNF-a, lL-1b and NO may play in producing cardiac decompensation in human septic shock, little is known with regard to mechanism(s) by which bacterial pathogens induce their expression in the heart. A major advance in the understanding of the early events in gram-positive bacterial signaling has been the identification of Toll-like receptors (TLRs). Recent studies suggest that TLR2 may be a pattern recognition receptor that binds gram-positive bacteria and their cell wall components. In addition, TLR2 is an effective signaling molecule that activates NF-kB, leading to cytokine production. The long-term objectives of this research initiative are not only to delineate the molecular pathogenesis of gram-positive septic shock, but also to develop strategies to prevent or attenuate the untoward effects of sepsis in the heart. Toward this end, the immediate specific objective of this application will be to delineate the role of TLR2 in the pathogenesis of myocardial dysfunction associated with gram-positive septic shock. Two closely interrelated hypotheses will be tested: first, signaling via TLR-2 is responsible, at least in part, for the induction of proinflammatory mediators associated with myocardial inflammation following infection with the gram-positive bacterium Staphylococcus aureus; second, TLR2 is responsible, at least in part, for the development of or S. aureus-induced left ventricular contractile dysfunction. These hypotheses will be tested in three Specific Aims. Specific Aim 1 will determine whether TLR2 mediates the inflammatory response induced by gram-positive bacteria in the heart. Specific Aim 2 will determine whether TLR2 mediates the cardiac response following infection with S. aureus. Specific Aim 3 will determine whether immunotherapeutic interventions designed to interdict signaling via TLR2 prevent and/or modify left ventricular dysfunction in gram-positive septic shock. These studies will provide definitive new information with respect to the mechanisms responsible for the deleterious effects of gram-positive sepsis on cardiac function and structure.

描述（由申请人提供）：诱发的系统性炎症反应 革兰氏阳性细菌与相当大的发病率有关 死亡率归因于难治性低血压，心脏功能障碍和 多器官故障。尽管TNF-A，LL-1B有潜在的重要作用 没有可能在人类败血性冲击中产生心脏代表性， 关于细菌病原体诱导的机制知之甚少 他们在心中的表情。理解 革兰氏阳性细菌信号传导的早期事件已成为识别 Toll样受体（TLR）。最近的研究表明，TLR2可能是 结合革兰氏阳性细菌及其细胞的图案识别受体 墙部组件。另外，TLR2是一个有效的信号分子 激活NF-KB，导致细胞因子产生。长期目标 该研究计划不仅要描述分子发病机理 革兰氏阳性的败血性休克，也可以制定预防或 减轻败血症心脏中不良影响。在这一目标中， 本应用的直接特定目标将是描述角色 TLR2在与心肌功能障碍的发病机理中 革兰氏阳性败血性休克。将检验两个密切相互关联的假设： 首先，通过TLR-2信令至少部分负责感应 与心肌炎症相关的促炎性介质之后 革兰氏阳性细菌金黄色葡萄球菌感染；第二，TLR2 至少部分是针对金黄色葡萄球菌诱导的 左心室收缩功能障碍。这些假设将在 三个具体目标。具体目标1将确定TLR2是否介导 革兰氏阳性细菌在心脏中引起的炎症反应。具体的 AIM 2将确定TLR2是否介导心脏反应 金黄色葡萄球菌感染。特定目标3将确定是否 免疫治疗干预措施旨在通过TLR2阻止信号传导 预防和/或修饰革兰氏阳性化粪池中的左心室功能障碍 震惊。这些研究将提供有关的确切新信息 革兰氏阳性败血症的有害作用的机制 关于心脏功能和结构。