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

描述（由申请人提供）：诱导的全身炎症反应 由革兰氏阳性菌引起的感染与相当大的发病率有关， 归因于顽固性低血压、心功能不全和 多器官衰竭尽管TNF-α、IL-1b 并且NO可能在人类感染性休克中产生心脏失代偿中起作用， 关于细菌性病原体诱导 他们心中的表情。在对人类的理解上的一个重大进步 革兰氏阳性细菌信号传导的早期事件已经被鉴定为 Toll样受体（TLR）。最近的研究表明，TLR 2可能是一种 结合革兰氏阳性菌及其细胞的模式识别受体 墙组件。此外，TLR 2是一种有效的信号分子， 激活NF-kB，导致细胞因子产生。的长期目标 这项研究不仅是为了描述 革兰氏阳性菌感染性休克，但也制定战略，以防止或 减轻败血症在心脏中的不良影响。为此， 本申请的直接具体目标将是描述 TLR 2在心肌功能障碍发病机制中的作用 革兰氏阳性菌感染性休克将检验两个密切相关的假设： 首先，通过TLR-2的信号传导至少部分地负责诱导 与心肌炎症相关的促炎介质 感染革兰氏阳性细菌金黄色葡萄球菌;第二，TLR 2 至少部分负责或S的开发。金黄色诱导的 左心室收缩功能障碍。这些假设将在 三个具体目标。特异性目的1将决定TLR 2是否介导 革兰氏阳性菌引起的心脏炎症反应。具体 目的2将确定TLR 2是否介导心脏反应， 链球菌感染金黄色。具体目标3将确定是否 旨在阻断TLR 2信号传导的免疫干预 预防和/或改善革兰氏阳性脓毒症患者的左心室功能障碍 冲击.这些研究将提供关于以下方面的明确的新信息： 革兰氏阳性脓毒症有害作用的机制 对心脏功能和结构的影响

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.