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 导致剩余组织上的负荷增加。这种负载的变化 启动修复和补偿信号通路， 决定了病理性左心室重构的程度， 缺血和再灌注。应激激活的细胞因子，包括白细胞介素-1 参与缺血和再灌注后的早期信号事件。 我们确定了白细胞介素-1受体家族成员T1/ST 2，作为一个基因， 机械牵拉和白介素-1对心肌细胞凋亡的诱导作用 肌细胞T1/ST 2以前没有报道在心脏中表达。 肌细胞，但其生长和免疫功能的细胞类型以外的 心血管系统结合我们在心肌细胞中的新发现 提示T1/ST 2可能是免疫/炎症之间界面分子 反应和肌细胞存活 缺血再灌注后。本提案的目标是 关于这种先前被归类为免疫系统的功能的关键问题 心肌缺血时应激激活通路中的功能基因， 再灌注可能影响肌细胞存活。 在具体目标1中，我们将研究T1/ST 2的诱导和信号传导， 心肌细胞缺氧/复氧时其与心肌细胞存活的偶联 体外培养心肌细胞。在具体目标2中，TI/ST 2缺失小鼠将经受 心肌缺血和再灌注，以确定心肌细胞TI/ST 2的作用 生存和重塑。在具体目标3中，我们将T1/ST 2基因 直接进入缺血的T1/ST 2缺失小鼠的心肌， 再灌注和检查心肌细胞存活和心室重塑。在 具体目的4我们提出鉴定T1/ST 2的肽配体及其 缺血期间对心肌的影响， 再灌注

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.