Role of Toll-Like Receptor Signaling in Cardiac Ischemia

描述（由申请人提供）：越来越多的证据表明，由先天免疫系统启动的炎症途径在心血管疾病中起作用。然而，这些先天免疫途径参与心脏病的机制尚未阐明。我们的长期目标是阐明与心肌缺血/再灌注（I/R）损伤相关的免疫调节和促炎信号机制。本研究主要关注toll样受体（TLR）介导的信号通路在心肌I/R损伤中的作用。Toll受体是一个古老且进化保守的信号转导分子家族，对诱导先天免疫和炎症至关重要。主要假设是：i) TLR介导的信号通路在i /R后的免疫和炎症反应调节中起关键作用；ii)特定TLR信号通路的调节将保护心肌免受i /R损伤。提出这项研究的基本原理是，我们有初步数据表明，TLR信号通路在心肌I/R损伤中起重要作用。为了批判性地评估这些假设，我们将追求四个具体目标。具体目标明确TLR介导的myd88依赖性信号在心肌I/R损伤中的作用。我们将确定TLR介导的myd88依赖信号的抑制是否会增强或抑制心脏损伤和功能恢复。具体目标2。探讨TLR介导的PI3K/Akt信号在心肌I/R损伤中的作用。PI3K/Akt信号是TLR介导的信号通路，不通过MyD88。我们将确定激活或抑制PI3K活性是否会保护或增强心肌I/R损伤。具体目标3。确定TLR介导的myd88依赖通路和PI3K/Akt通路在I/R后心肌损伤中的调节作用。我们将确定同时阻断TLR介导的MyD88依赖通路和激活PI3K/Akt信号是否能产生最大的心脏保护作用。具体目标阐明TLR激动剂的心脏保护机制。LPS是一种TLR4激动剂，需要至少8小时的预处理才能诱导心脏保护。磷酸葡聚糖是一种TLR2激动剂，在缺血之前或之后立即给予可迅速保护心脏免受I/R损伤。我们将使用这些TLR特异性激动剂作为工具来剖析对I/R损伤至关重要的免疫信号通路。

DESCRIPTION (provided by applicant): A growing body of evidence suggests that there is a role for inflammatory pathways, initiated by the innate immune system, in cardiovascular disease. However, the mechanisms by which these innate immune pathways participate in heart disease have not been elucidated. Our long-term goal is to elucidate the immunoregulatory and pro-inflammatory signaling mechanisms associated with myocardial ischemia/reperfusion (I/R) injury. This proposal focuses on the role of Toll-like receptor (TLR) mediated signaling pathways in myocardial I/R injury. Toll receptors are an ancient and evolutionarily conserved family of signal transducing molecules which are critical for the induction of innate immunity and inflammation. The central hypotheses are: i) TLR mediated signaling pathways play a pivotal role in regulating immune and inflammatory responses following I/R and ii) modulation of specific TLR signaling pathways will protect the myocardium from I/R injury. The rationale for the proposed studies is that we have preliminary data suggesting that TLR signaling pathways play an important role in myocardial I/R injury. To critically evaluate the hypotheses we will pursue four specific aims. Specific Aim 1. Define the role of TLR mediated MyD88-dependent signaling in myocardial I/R injury. We will determine whether inhibition of TLR mediated MyD88-dependent signaling enhances or suppresses cardiac injury and functional recovery. Specific Aim 2. Investigate the role of TLR mediated PI3K/Akt signaling in myocardial I/R injury. PI3K/Akt signaling is a TLR mediated pathway, that does not signal through MyD88. We will determine whether activation or inhibition of PI3K activity will protect or enhance myocardial I/R injury. Specific Aim 3. Determine the effects of modulation of TLR mediated MyD88-dependent and PI3K/Akt pathways on myocardial injury following I/R. We will determine whether simultaneously blocking TLR mediated MyD88- dependent pathway and activating PI3K/Akt signaling could result in maximal cardioprotection. Specific Aim 4. Elucidate the cardioprotective mechanisms of TLR agonists. LPS, a TLR4 agonist requires at least 8 hrs of pretreatment to induce cardioprotection. Glucan phosphate, a TLR2 agonist, rapidly protects the heart from I/R injury when administered immediately before or after ischemia. We will employ these TLR specific agonists as tools to dissect the immune signaling pathways which are critical to I/R injury.