Role of the T1/ST2 receptor in myocardial ischemia/repe*

描述(由申请人提供)： 心肌缺血和再灌注导致存活心肌的丧失 导致剩余组织的负荷增加。这一负载变化 启动修复和补偿信号通路，其成功 确定病理性左心室重构的程度 缺血和再灌流。包括白介素1在内的应激激活细胞因子 参与缺血再灌流后的早期信号事件。 我们鉴定出白介素1受体家族成员T1/ST2是一个基因 机械应激和白细胞介素1对心脏的高度诱导作用 肌细胞。T1/ST2基因在心脏组织中的表达尚未见报道 肌细胞，但它的生长和免疫功能在细胞类型之外 心血管系统与我们在心肌细胞中的新发现 提示T1/ST2可能是免疫/炎症之间的界面分子 反应与心肌细胞存活 在缺血和再灌流后。这项提案的目标是 关于这种先前分类的免疫功能的关键问题 心肌缺血应激激活通路中的功能基因 再灌流可能会影响心肌细胞的存活。 在特定的目标1中，我们将研究T1/ST2和ST2的诱导和信号转导 它与心肌细胞缺氧/复氧存活的偶联 体外培养的心肌细胞。在特定的目标2中，TI/ST2缺失的小鼠将受到 心肌缺血再灌流中TI/ST2在心肌细胞中的作用 生存和重建。在特定的目标3中，我们将传递T1/ST2基因 直接进入T1/ST2缺陷型小鼠的心肌 并检测心肌细胞存活率和心室重塑。在……里面 具体目标4我们建议鉴定T1/ST2的多肽配体及其 缺血再灌流对心肌的影响 再灌流。

DESCRIPTION (provided by applicant): Myocardial ischemia and reperfusion results in loss of viable myocardium leading to increased load on the remaining tissue. This change in load initiates reparative and compensatory signaling pathways, the success of which determines the extent of pathologic left ventricular remodeling following ischemia and reperfusion. Stress-activated cytokines including interleukin-1 participate in the early signaling events following ischemia and reperfusion. We identified an interleukin-1 receptor family member, T1/ST2, as a gene highly-induced by both mechanical strain and interdeukin-1 in cardiac myocytes. T1/ST2 has not previously been reported to be expressed in cardiac myocytes, but its growth and immune functions in cell types outside the cardiovascular system coupled with our novel findings in cardiac myocytes suggest that T1/ST2 may be an interface molecule between immune/inflammation responses and myocyte survival following ischemia and reperfusion. The aims in this proposal address critical questions regarding the function of this previously-classified immune function gene in stress-activated pathways during myocardial ischemia and reperfusion potentially affecting myocyte survival. In specific aim 1 we will examine the induction and signaling of T1/ST2 and its coupling to myocyte survival during hypoxia/reoxygenation in cardiac myocytes in vitro. In specific aim 2, TI/ST2 null mice will be subjected to myocardial ischemia and reperfusion to determine the role of TI/ST2 in myocyte survival and remodeling. In specific aim 3, we will deliver the T1/ST2 gene directly into the myocardium of T1/ST2 null mice subjected to ischemia and reperfusion and examine myocyte survival and ventricular remodeling. In specific aim 4 we propose to identify peptide ligands of T1/ST2 and their effects on the myocardium during ischemia and reperfusion.