TNFR1 and Sex Hormone Signaling in Myocardial Ischemia

描述（由申请人提供）：炎症细胞因子与急性手术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，现有的临床数据是混杂的。在促炎信号导致损伤的程度上，雌激素（和/或睾丸激素）对这些信号过程的影响可能部分解释了结果的差异，但更重要的是可能提供潜在治疗策略的见解。基于临床数据的明显权重，我们首先假设雌激素会引起心脏急性炎症，从而恶化恢复。我们的初步数据并不支持这个假设。基于我们已发表的研究背景，以及其他人的研究结果，我们假设TNFR1信号抗性发生在女性中，是通过雌激素受体α依赖的细胞内信号与TNFR1信号的串扰发生的。作为实现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性和女性以及TNFR1敲除男性和女性I/R后心肌促炎信号活性（例如p38 MAPK活性）和细胞因子（tnf - α, il -1 β, IL-6）产生的影响；2)确定睾酮对I/R后TNF受体介导的心肌功能障碍的影响，明确TNF抑制在下游细胞因子（IL-1、IL-6）产生和TNF自身扩增中的作用；3)在内源性睾酮或雌激素消耗和替代的男性和女性心脏中，通过Apaf-1、caspase-9、-8和-3的产生，测量TNFR1和性激素对凋亡信号的影响。

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.