TNRF1 Signaling Resistance in Ischemic Human Female Myocardium

描述(申请人提供)：心肌缺血损伤和心力衰竭机制的性别差异知之甚少。在文明国家，心肌缺血和再灌注损伤是导致心力衰竭和死亡的主要原因。肿瘤坏死因子可能在心力衰竭的发生发展中起重要作用。在人类中，功能能力、存活率和循环中的肿瘤坏死因子水平之间有直接的相关性。尽管动物研究非常鼓舞人心，但临床研究表明，简单地降低心力衰竭患者中肿瘤坏死因子的生物利用度总体上是有害的。这使人们认识到，肿瘤坏死因子本身可能具有有益或有害的影响，这取决于其受体(TNFR1或TNFR2)被激活。去除TNFR1基因可以钝化心力衰竭并提高存活率，而消融TNFR2基因则会加剧心力衰竭并降低存活率。因此，不同的肿瘤坏死因子受体激活可能是临床变异的一种解释，但除此之外，细胞内信号的不同可能有一个重要的影响。平衡肿瘤坏死因子信号以减少其有害影响，同时增强其有益作用，可能是治疗女性和男性心力衰竭的一种重要的新方法。一种这样的方法是通过抑制细胞因子信号蛋白(SoCs)对TNFR1信号的干扰。我们的初步数据表明，在女性心肌中存在TNFR1信号抵抗，这可能是由于雌激素受体介导的SOCS蛋白产生上调所致。心肌缺血后，女性心肌组织中的肿瘤坏死因子水平、心功能不全和细胞凋亡均减少。雌激素的耗尽或阻断消除了这一效应。然而，目前尚不清楚是否存在基于性别的TNFR1信号差异，如果存在，则这些差异发生的机制是什么。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TNFR1信号转导的串扰，在缺血时诱导雌性心肌(人、小鼠)相对的TNFR1信号抵抗。为了研究这一点，我们建议完成以下特定目标：1)确定在缺血时女性心肌(人、小鼠)是否存在TNFR1信号抵抗，如果是，是否通过内源性雌激素激活α或β雌激素受体来介导抵抗；2)女性心肌中的TNFR1信号抵抗是由雌激素受体通过STATS刺激细胞因子信号蛋白抑制物(SOCS 1、2和/或3)介导的；3)SOCS-3介导心肌缺血时的TNFR1信号抵抗；4)SOCS-3是雌激素诱导的TNFR1信号抵抗所必需的。将对以下研究对象的雌性和雄性心肌进行测试：人类、野生型小鼠、STATS基因敲除小鼠、TNFR1和TNFR2基因敲除小鼠，以及α和β雌激素受体基因敲除小鼠。

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.