TNRF1 Signaling Resistance in Ischemic Human Female Myocardium

描述（由申请方提供）：对心肌缺血性损伤和心力衰竭机制的性别差异了解甚少。心肌缺血和再灌注损伤是文明国家心力衰竭和死亡的主要原因。肿瘤坏死因子α（TNF）可能在心力衰竭的发展中起重要作用。在人类中，功能能力、存活率和循环TNF水平之间存在直接相关性。尽管动物研究非常令人鼓舞，但临床研究表明，简单地降低心力衰竭患者中TNF的生物利用度，总的来说是有害的。这导致了重要的认识，即TNF本身可能具有有益或有害的影响，这取决于其受体（TNFR 1或TNFR 2）被激活。TNFR 1基因的消融减弱心力衰竭并提高存活率，而TNFR 2基因的消融加剧心力衰竭并降低存活率。因此，不同的TNF受体活化可能是临床变异的一种解释，但是，此外，不同的细胞内信号传导可能具有重要的影响。失衡TNF信号以减少其有害作用同时增强其有益作用可能是治疗女性和男性心力衰竭的重要新方法。一种这样的方法是通过抑制细胞因子信号传导蛋白（SOCS）破坏TNFR 1信号传导。我们的初步数据表明，TNFR 1信号传导阻力发生在女性心肌，这可能是由于雌激素受体介导的上调SOCS蛋白的生产。心肌缺血后，女性心肌中TNF水平、心室功能障碍和细胞凋亡减少。消耗或阻断雌激素可消除这种效应。然而，TNFR 1信号传导中是否存在基于性别的差异，以及如果存在，它们发生的机制仍然未知。我们假设内源性雌激素通过雌激素受体（α和/或β）刺激SOCS蛋白（1、2和/或3）与TNFR 1信号转导的串扰，在缺血期间诱导女性心肌（人、小鼠）中TNFR 1信号转导的相对抗性。为了研究这一点，我们建议完成以下具体目标：以确定是否：1）TNFR 1信号传导阻力发生在女性心肌（人，小鼠），如果是，抗性是否由α或β雌激素受体的内源性雌激素活化介导; 2）雌激素受体刺激细胞因子信号抑制蛋白介导女性心肌TNFR 1信号抵抗S 0 CS-1、S 0 CS-2和/或S 0 CS-3通过STATS介导TNFR 1信号传导抗性; 3）S 0 CS-3介导心肌缺血期间的TNFR 1信号传导抗性; 4）S 0 CS-3是雌激素诱导的TNFR 1信号传导抗性所需的。将检测以下研究受试者的雌性和雄性心肌：人、野生型小鼠、STATS敲除小鼠、TNFR 1和TNFR 2敲除小鼠以及α和β雌激素受体敲除小鼠。

DESCRIPTION (provided by applicant): Sex differences in the mechanisms of myocardial ischemic injury and heart failure are poorly understood. Myocardial ischemia and reperfusion injury is a leading cause of heart failure and death in civilized countries. Tumor necrosis factor alpha (TNF) may play an important role in the development of heart failure. In humans, there is a direct correlation between functional capacity, survival, and circulating TNF levels. Although animal studies were very encouraging, clinical studies indicated that simply decreasing the bioavailability of TNF in heart failure patients was, on balance, detrimental. This led to the important appreciation that TNF itself may have beneficial or detrimental effects depending on which of its receptors (TNFR1 or TNFR2) is activated. Ablation of the TNFR1 gene blunts heart failure and improves survival, whereas ablation of the TNFR2 gene exacerbates heart failure and reduces survival. Differential TNF receptor activation may therefore be one explanation for clinical variation, but, in addition, differential intracellular signaling may have an important effect. Unbalancing TNF signaling to diminish its deleterious effects while enhancing its salutary effects may be an important new approach to the treatment of heart failure in females and males. One such approach is through suppression of cytokine signaling proteins (SOCS) disruption of TNFR1 signaling. Our preliminary data suggests that TNFR1 signaling resistance occurs in female myocardium which may be due to estrogen receptor mediated upregulation of SOCS protein production. After myocardial ischemia, TNF levels, ventricular dysfunction, and apoptosis are decreased in female myocardium. Depletion or blockade of estrogen abolished this effect. It remains unknown, however, whether gender based differences in TNFR1 signaling exist, and if so, the mechanisms by which they occur. We hypothesize that endogenous estrogen induces relative TNFR1 signaling resistance in female myocardium (human, mouse) during ischemia by estrogen receptor (alpha and/or beta) stimulation of SOCS protein (1, 2, and/or 3) crosstalk with TNFR1 signal transduction. To study this we propose the completion of the following specific aims: To determine whether; 1) TNFR1 signaling resistance occurs in female myocardium (human, mouse) during ischemia, and if so, whether resistance is mediated by endogenous estrogen activation of alpha or beta estrogen receptors; 2) TNFR1 signaling resistance in female myocardium is mediated by estrogen receptor stimulation of suppressor of cytokine signaling proteins (SOCS 1, 2, and/or 3) through STATS; 3) SOCS-3 mediates TNFR1 signaling resistance during myocardial ischemia; 4) SOCS-3 is required for estrogen induced TNFR1 signaling resistance. Female and male myocardium from the following study subjects will be tested: humans, wild type mice, STATS knockout mice, TNFR1 and TNFR2 knockout mice, and alpha and beta estrogen receptor knockout mice.