TNFR1 and Sex Hormone Signaling in Myocardial Ischemia

心肌缺血中的 TNFR1 和性激素信号传导

• 批准号: 7115118
• 负责人: TROY A MARKEL
• 金额: $ 4.88万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-07 至 2008-08-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7115118
• 关键词: apoptosis; cysteine endopeptidases; cytokine receptors; estrogen receptors; estrogens; gender difference; genetically modified animals; heart function; hormone regulation /control mechanism; inflammation; interleukin 1; interleukin 6; laboratory mouse; laboratory rat; male castration; mitogen activated protein kinase; myocardial ischemia /hypoxia; myocardium disorder; ovariectomy; postdoctoral investigator; protein structure function; sex hormones; testosterone; tumor necrosis factor alpha

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.

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着深远的影响。事实上，临床结局似乎受到患者性别的影响;然而，现有的临床数据是混合的。在某种程度上，促炎信号有助于损伤，雌激素（和/或睾酮）对这些信号传导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对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的急性炎症，从而恶化恢复。我们的初步数据并不支持这一假设。基于我们发表的研究结果的背景，以及其他人的研究结果，我们的假设是TNFR 1信号传导抗性通过雌激素受体α依赖性细胞内信号传导与TNFR 1信号传导的串扰发生在女性中。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心肌促炎信号传导活性的影响。（例如p38 MAPK活性）和细胞因子I/R后野生型雄性和雌性以及TNFR 1敲除雄性和雌性中的（TNF-α、IL-1 β、IL-6）产生; 2）确定睾酮对I/R后TNF受体介导的心肌功能障碍的影响，并确定TNF抑制在下游细胞因子中的作用。（IL-1、IL-6）产生和TNF自身扩增; 3）测量TNFR 1和性激素对经由Apaf-1、半胱天冬酶-9、在雄性和雌性心脏中产生内源性睾酮或雌激素耗竭和替代。