TNRF1 Signaling Resistance in Ischemic Human Female Myocardium

描述（由申请人提供）：性别差异在心肌缺血损伤和心力衰竭的机制尚不清楚。心肌缺血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生发展中起重要作用。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，总体而言，单纯降低心力衰竭患者TNF的生物利用度是有害的。这导致了重要的认识，TNF本身可能有有益或有害的影响取决于其受体（TNFR1或TNFR2）的哪个被激活。消融TNFR1基因可减轻心衰并提高生存率，而消融TNFR2基因可加重心衰并降低生存率。因此，TNF受体的差异激活可能是临床变异的一种解释，但除此之外，细胞内信号的差异可能具有重要作用。不平衡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。其中一种方法是通过抑制细胞因子信号蛋白（SOCS）破坏TNFR1信号。我们的初步数据表明，TNFR1信号抗性发生在女性心肌中，这可能是由于雌激素受体介导的SOCS蛋白产生上调。心肌缺血后，女性心肌TNF水平、心室功能障碍和细胞凋亡均降低。雌激素的消耗或阻断消除了这种作用。然而，TNFR1信号是否存在基于性别的差异，如果存在，其发生的机制尚不清楚。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，诱导女性心肌（人、小鼠）缺血时的相对TNFR1信号抗性。为此，我们提出完成以下具体目标：确定是否；1)女性心肌（人、小鼠）缺血时是否发生TNFR1信号抵抗，如果发生，是否通过内源性雌激素激活α或β雌激素受体介导抵抗；2)女性心肌TNFR1信号抗性是雌激素受体通过STATS刺激细胞因子信号蛋白抑制因子（SOCS 1、2和/或3）介导的；3)心肌缺血时，SOCS-3介导TNFR1信号抵抗；4)雌激素诱导的TNFR1信号抗性需要SOCS-3。研究对象为：人类、野生型小鼠、STATS敲除小鼠、TNFR1和TNFR2敲除小鼠、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.