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

T1/ST2 受体在心肌缺血/重复中的作用*

• 批准号: 6442728
• 负责人: ELLEN O WEINBERG
• 金额: $ 41.35万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-25 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6442728
• 关键词: cardiac myocytes; cell death; cell growth regulation; cytokine receptors; interleukin 1; laboratory mouse; ligands; myocardial ischemia /hypoxia; receptor expression; regeneration; reperfusion

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.

描述（由申请人提供）： 心肌缺血和再灌注导致存活心肌丧失 导致剩余组织的负荷增加。这种负载变化 启动修复和补偿信号通路，其成功 决定病理性左心室重构的程度 缺血和再灌注。应激激活细胞因子，包括白细胞介素 1 参与缺血和再灌注后的早期信号事件。 我们鉴定出白细胞介素 1 受体家族成员 T1/ST2 作为基因 心脏中机械应变和白细胞介素-1 高度诱导 肌细胞。此前尚未有报道称 T1/ST2 在心脏中表达 肌细胞，但其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相结合 表明T1/ST2可能是免疫/炎症之间的界面分子 反应和肌细胞存活 缺血和再灌注后。本提案的目标 关于这种先前分类的免疫功能的关键问题 心肌缺血期间应激激活途径中的功能基因 再灌注可能影响肌细胞的存活。 在具体目标 1 中，我们将检查 T1/ST2 的诱导和信号传导以及 心脏缺氧/复氧期间其与心肌细胞存活的耦合 体外的肌细胞。在具体目标 2 中，TI/ST2 无效小鼠将接受 心肌缺血和再灌注以确定 TI/ST2 在肌细胞中的作用 生存与重塑。在具体目标3中，我们将提供T1/ST2基因 直接进入缺血的 T1/ST2 缺失小鼠的心肌并 再灌注并检查心肌细胞存活和心室重塑。在 具体目标 4 我们建议鉴定 T1/ST2 的肽配体及其 缺血时对心肌的影响 再灌注。