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）：心肌缺血损伤机制和心力衰竭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）可能在心力衰竭发展中起重要作用。在人类中，功能能力，存活和循环TNF水平之间存在直接相关。尽管动物研究非常令人鼓舞，但临床研究表明，仅降低心力衰竭患者中TNF的生物利用度是有害的。这导致了一个重要的欣赏，即TNF本身可能会根据其受体（TNFR1或TNFR2）的哪些受体具有有益或有害影响。 TNFR1基因的消融会钝化心力衰竭并提高生存率，而TNFR2基因的消融会加剧心力衰竭并降低生存率。因此，差异TNF受体激活可能是临床变异的一种解释，但此外，差异细胞内信号传导可能具有重要作用。不平衡的TNF信号传导减少其有害影响的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方法。一种方法是抑制TNFR1信号传导的细胞因子信号蛋白（SOCS）破坏。我们的初步数据表明，TNFR1信号耐药性发生在雌性心肌中，这可能是由于雌激素受体介导的SOCS蛋白质产生的上调。在心肌缺血后，雌性心肌症状降低后，TNF水平，心室功能障碍和凋亡减少。雌激素的耗尽或阻滞消除了这种作用。然而，是否存在基于性别的TNFR1信号传导的差异，如果是这样，则其发生的机制是否存在。我们假设内源性雌激素会通过雌激素受体（Alpha和/或β）刺激SOCS蛋白（1、2和/或3）crosstalk诱导雌激素受体（Alpha和/或β）在缺血期间雌性心肌（人，小鼠）的相对TNFR1信号传导抗性。为了研究这一点，我们建议完成以下特定目的：确定是否； 1）在缺血期间，雌性心肌（人，小鼠）发生TNFR1信号抗性，如果是这样，是否是由α的内源性雌激素激活或β雌激素受体激活介导的。 2）雌性心肌的TNFR1信号耐药性是通过统计数据刺激细胞因子信号蛋白（SOCS 1，2和/或3）的雌激素受体刺激。 3）SOCS-3介导心肌缺血期间TNFR1信号抗性； 4）SOCS-3是雌激素诱导的TNFR1信号抗性所必需的。将测试以下研究对象的雌性和雄性心肌：人类，野生型小鼠，统计敲除小鼠，TNFR1和TNFR2敲除小鼠，以及α和β雌激素受体敲除小鼠。