TNRF1 Signaling Resistance in Ischemic Human Female Myocardium

人类女性缺血心肌中的 TNRF1 信号传导抵抗

基本信息

批准号：
7797542
负责人：
DANIEL R MELDRUM
金额：
$ 44.99万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-16 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7797542
关键词：
Ablation Activities of Daily Living Animals Apoptosis Back Biological Availability Cardiac Myocytes Cessation of life Clinical Clinical Research Country Cytokine Inducible SH2-Containing Protein Cytokine Signaling Data Development Equilibrium Estradiol Estrogen Receptor 2 Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens Female Gender Genes Heart failure Hormones Human Injury Ischemia Knock-out Knockout Mice Mediating Mental Depression Methods Mus Myocardial Myocardial Ischemia Myocardial tissue Myocardium Patients Play Production Proteins RNA Interference Receptor Activation Relative (related person)Reperfusion Injury Reperfusion Therapy Research Personnel Resistance Role Sex Characteristics Signal Transduction Signaling Protein Small Interfering RNA Study Subject TNFRSF1A gene TNFRSF1B gene Testing Tumor Necrosis Factor-alpha Up-Regulation Variant Ventricular Dysfunction Wild Type Mouse base human TNFRSF1A protein human female improved in vivo male novel strategies programs protein expression receptor tumor necrosis factor alpha receptor

项目摘要

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.

描述（由申请人提供）：对心肌缺血性损伤和心力衰竭机制的性别差异知之甚少。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生过程中发挥重要作用。在人类中，功能能力、生存率和循环 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 的生物利用度总体而言是有害的。这导致人们认识到 TNF 本身可能具有有益或有害的作用，具体取决于其受体（TNFR1 或 TNFR2）被激活。 TNFR1 基因的消融可减轻心力衰竭并提高生存率，而 TNFR2 基因的消融则会加剧心力衰竭并降低生存率。因此，差异性 TNF 受体激活可能是临床变异的一种解释，但此外，差异性细胞内信号传导可能具有重要影响。不平衡 TNF 信号传导以减少其有害作用，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) 来破坏 TNFR1 信号传导。我们的初步数据表明，女性心肌中出现 TNFR1 信号传导抵抗，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，女性心肌中 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，目前尚不清楚 TNFR1 信号传导是否存在基于性别的差异，如果存在，其发生的机制又如何。我们假设内源性雌激素在缺血期间通过雌激素受体（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）相对TNFR1信号传导抵抗。为了研究这一点，我们建议完成以下具体目标：确定是否； 1）缺血期间雌性心肌（人、小鼠）中出现TNFR1信号传导抵抗，如果是，抵抗是否是由α或β雌激素受体的内源性雌激素激活介导的； 2）女性心肌中TNFR1信号传导抵抗是由雌激素受体通过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）SOCS-3在心肌缺血过程中介导TNFR1信号传导抵抗； 4) SOCS-3是雌激素诱导的TNFR1信号传导抵抗所必需的。将测试以下研究对象的雌性和雄性心肌：人类、野生型小鼠、STATS 敲除小鼠、TNFR1 和 TNFR2 敲除小鼠以及 α 和 β 雌激素受体敲除小鼠。