Molecular Mechanisms of Stress Signaling in the Female Heart

项目摘要/摘要 与男性相比，35-50岁女性的心脏病发病率有所上升。 年龄相仿。与男性相比，女性心脏病发作后死亡和并发症的风险更高。 由于妇女在临床试验中的代表性不足，缺乏针对性别量身定做的药物 妇女可能比男子更容易受到传统和新出现的风险因素的影响。 压力已成为女性心脏病的重要风险因素；压力水平已被证明是 与女性心脏病发作后恢复延迟、复发和死亡率增加有关。性 荷尔蒙被认为是男性和女性生理差异的关键调节因素 健康和疾病。这些荷尔蒙当然会导致心脏病中的性二型性；然而， 性别对心脏病发作的发生率和结局的影响更为复杂，不太可能起到应有的作用 单单是性激素。本提案的目标是定义潜在的信号通路之一 在心肌缺血(心脏病发作)的背景下，应激对女性心脏健康的有害影响。至 为了实现这一目标，我们建议研究糖皮质激素(主要应激) 激素)通过抑制5-羟色胺活性影响雌激素对心肌缺血的心脏保护作用 糖皮质激素抑制雌激素对心肌细胞5-羟色胺受体转录调控的影响 HT2BR(通过调节心肌细胞的线粒体功能参与心脏保护)。一个 5-羟色胺活性降低与抑郁症患者心肌梗死风险增加有关 患者以及5-羟色胺受体基因多态性与糖皮质激素反应升高相关 与心血管并发症有关，包括心脏病发作的发生率增加。因此，我们的目标是 雌激素对心脏5-HT2BR表达的调节机制及糖皮质激素的影响 雌激素介导的5-HT2BR信号在缺血/再灌注中的作用我们假设压力会施加在 心肌梗死加重线粒体功能障碍对女性心脏的不良影响 糖皮质激素抑制心肌细胞雌激素对5-HT2BR转录的调节。我们会调查的 这一途径是通过检测心肌细胞中糖皮质激素和雌激素拮抗作用来实现的。 I/R中的串扰(体内研究)以及雌激素调节5-HT2BR的分子和生理效应 在缺血条件下的线粒体功能。如果得到资助，这个应用程序将帮助我开发一种科学的 独立项目，接受心血管领域的培训，建立研究团队，加强指导 技能，并提高我的拨款撰写技能，以变得有竞争力，申请主要的资助机制。我的 目前的机构和我的导师和共同导师将为我提供必要的设施和指导，以 完成这些目标。此外，我还将参加培训和职业发展活动，这将加强 我的科学生涯。

Project Summary/Abstract The prevalence of heart attacks has increased among women between 35-50 years of age compared to men of the same age. In contrast to men, women have a higher risk of mortality and complications after a heart attack due to the under-representation of women in clinical trials, the lack of gender-tailored pharmacological treatments, and potential higher vulnerability of women than for men to traditional and emerging risk factors. Stress has emerged as an important risk factor for heart disease in women; stress levels have been shown to correlate with delayed recovery, recurrence, and increased mortality after a heart attack in women. Sex hormones are considered the critical regulators of the physiological differences between men and women in health and disease. These hormones certainly contribute to sexual dimorphism in heart disease; however, the effects of gender on the incidence and outcomes of a heart attack are more complex and are unlikely to be due to sex hormones alone. The goal of the present proposal is to define one of the signaling pathways underlying the deleterious effects of stress on female cardiac health in the setting of myocardial ischemia (heart attack). To accomplish this goal, we propose to investigate the mechanisms whereby glucocorticoids (the primary stress hormones) affects estrogen cardioprotection in myocardial ischemia by repressing serotonin activity in cardiomyocytes via glucocorticoid inhibition of estrogen transcriptional regulation of the serotonin receptor 5- HT2BR (implicated in cardioprotection through the regulation of mitochondrial function in cardiomyocytes). A decrease in serotonin activity has been associated with increased risk of myocardial infarction in depressed patients, and also polymorphisms in serotonin receptors are associated with elevated glucocorticoid response linked to cardiovascular complications, including an increased incidence of heart attacks. Therefore, we aim to elucidate estrogen regulatory mechanism of 5-HT2BR expression in the heart and the effects of glucocorticoids on estrogen-mediated 5-HT2BR signaling in ischemia/reperfusion (I/R). We hypothesize that stress exerts deleterious effects on the female heart in myocardial infarction by exacerbating mitochondrial dysfunction via glucocorticoids inhibition of estrogen transcriptional regulation of 5-HT2BR in cardiomyocytes. We will investigate this pathway by examining glucocorticoid and estrogen antagonism in cardiomyocytes, the effects of this crosstalk in I/R (in vivo studies), and the molecular and physiological effects of 5-HT2BR regulation by estrogen in mitochondrial function in ischemic conditions. If funded, this application will help me develop a scientifically independent project, acquire training in the cardiovascular field, build a research team, enhance my mentoring skills, and improve my grant writing skills to become competitive to apply to a major funding mechanism. My current institution and my mentor and co-mentor will provide me with the necessary facilities and guidance to accomplish these goals. Also, I will participate in training and career development activities that will strengthen my scientific career.