TNFR1 and Sex Hormone Signaling in Myocardial Ischemia

描述(由申请人提供)：炎性细胞因子与急性外科缺血后心肌损伤的发病机制有关。性激素对炎症过程有深远的影响。事实上，临床结果似乎受到患者性别的影响；然而，现有的临床数据喜忧参半。就促炎信号对损伤的影响而言，雌激素(和/或睾酮)对这些信号过程的影响可能部分解释了结果的差异，但更重要的是，可能为潜在的治疗策略提供了洞察。根据临床数据的明显权重，我们首先假设雌激素会引发心脏的急性炎症，从而使康复变差。我们的初步数据不支持这一假设。根据我们已发表的研究结果的背景，以及其他人的发现，我们的假设是，在女性中，TNFR1信号抵抗是通过依赖雌激素受体α的细胞内信号与TNFR1信号的串扰而发生的。作为这一目标的重大进展，我们将：1)确定性别和内源性睾酮或雌激素对野生型男女和TNFR 1基因敲除男女I/R后心肌促炎症信号活性(如p38MAPK活性)和细胞因子(肿瘤坏死因子-α、IL-1β、IL-6)产生的影响；2)确定睾酮对肿瘤坏死因子受体(S)介导的I/R后心肌功能障碍的影响，并明确肿瘤坏死因子抑制在下游细胞因子(IL-1、IL-6)产生和肿瘤坏死因子自身放大中的作用；3)检测在内源性睾酮或雌激素耗竭和替代作用下，TNFR1和性激素对Apaf-1、caspase-9、-8和-3产生的凋亡信号的影响。

DESCRIPTION (provided by applicant): Inflammatory cytokines have been implicated in the pathogenesis of myocardial injury following acute surgical ischemia. Sex hormones have a profound influence over inflammatory processes. Indeed, clinical outcomes appear to be influenced by patient gender; however, the available clinical data are mixed. To the extent that proinflammatory signaling contributes to injury, estrogen's (and/or testosterone's) effects on these signaling processes may in part explain differences in outcomes, but more importantly may provide insight into potential therapeutic strategies. Based on the apparent weight of the clinical data, we first hypothesized that estrogen would provoke acute inflammation in the heart, and thereby worsen recovery. Our preliminary data did not support that hypothesis. Based on the background of our published findings, as well as the findings of others, our hypothesis is TNFR1 signaling resistance occurs in females by estrogen receptor alpha dependent intracellular signaling crosstalk with the TNFR1 signaling. As significant advancements towards this goal we will: 1) determine the effect of gender and endogenous testosterone or estrogen on myocardial proinflammatory signaling activity (e.g. p38 MAPK activity) and cytokine (TNF-alpha, IL-1beta, IL-6) production after I/R in wild type males and females and TNFR1 knockout males and females; 2) determine the effect of testosterone on TNF receptor(s) mediated myocardial dysfunction following I/R and define the role of TNF inhibition in downstream cytokine (IL-1, IL-6) production and TNF auto-amplification; 3) Measure the effect of TNFR1 and sex hormones on apoptotic signaling via Apaf-1, caspase-9, -8 and -3 production in male and female hearts subjected to endogenous testosterone or estrogen depletion and replacement.