Gender differences and endothelin responses in right ventricular afterload stress

描述（由申请人提供）：本提案的目的是培养Anna Hemnes博士的科学发展和研究技能，使她成为一名独立的研究者。Hemnes博士目前在范德比尔特大学医学中心（VUMC）肺研究中心发展她的学术生涯。VUMC通过其众多的实验室资源，教育机会和专家教师提供了一个有利于发展医师科学家的环境。在John Newman博士的指导下，Hemnes博士将设计和执行实验，以提高她在右心室后负荷应激反应病理生物学方面的知识和研究技能。通过实验室经验和正式课程，她将获得实验设计和执行、转基因小鼠模型使用、细胞和分子生物学技术、统计分析和数据报告等方面的专业知识。这些技能将为Hemnes博士在右心室研究方面追求独立的学术生涯提供基础。右心室应激反应是晚期肺动脉高压患者生存的主要决定因素，但由于非标准肺血管阻塞导致右心室应激，研究很少。我们建立了一个右心室肥大的模型，通过捆绑肺动脉。在初步数据中，我们提出证据表明，RV后负荷应激反应是性别依赖的，性别改变RV对内皮素拮抗剂的反应。我们假设雌激素在RV对后负荷应激的反应中具有保护作用，内皮素和性激素相互作用，使RV对后负荷应激产生形态、生理和生化反应，这在男性和女性中是不同的。为了验证这一假设，我们制定了以下具体目标：1)在这种情况下，确定性激素对后负荷诱导的右心室肥大和内皮素信号的影响；2)确定内皮素对负荷应激后心室和心肌细胞内雌激素信号的影响。右心室衰竭是许多心肺疾病的重要后果，也是死亡率的主要决定因素。RV对后负荷应激反应的性别差异有待进一步探讨和解释。人类女性对多环芳烃的高易感性和内皮素阻断在肺动脉高压中的应用使本研究具有临床意义和生物学意义。

DESCRIPTION (provided by applicant): The purpose of this proposal is to cultivate the scientific development and advance the research skills of Dr. Anna Hemnes, so that she may become an independent investigator. Dr. Hemnes is currently developing her academic career in the Center for Lung Research at Vanderbilt University Medical Center (VUMC). VUMC provides an environment conducive to developing physician-scientists through its many laboratory resources, educational opportunities, and expert faculty. Under guidance by Dr. John Newman, Dr. Hemnes will design and perform experiments that will enhance her knowledge and research skills in the pathobiology of right ventricular response to afterload stress. Through laboratory experience and formal coursework, she will gain expertise in experimental design and execution, transgenic murine model use, cell and molecular biology techniques, statistical analysis, and data reporting. These skills will provide the foundation for Dr. Hemnes to pursue an independent academic career in right ventricular research. Right ventricular (RV) stress responses are a major determinant of survival in advanced pulmonary hypertension but little studied due to non-standard pulmonary vascular obstruction leading to right ventricular stress. We have developed a model of RV hypertrophy by banding the main pulmonary artery. In preliminary data we present evidence that RV afterload stress responses are gender dependent and that gender alters RV response to endothelin antagonism. We hypothesize that estrogen is protective in the RV responses to afterload stress and that endothelin and sex hormones interact to generate morphologic, physiologic, and biochemical RV responses to afterload stress that are different in males and females. To test this hypothesis, we have developed the following specific aims: 1) To determine the effects of sex hormones on afterload-induced RV hypertrophy and modification endothelin signaling in RV cardiomyocytes in this context; 2) To define the effects of endothelin on the afterload-stressed RV and on intracellular estrogen signaling within the cardiomyocyte. RV failure is an important consequence of many cardiopulmonary disorders and a major determinant of mortality. The gender differences in RV response to afterload stress require further exploration and explanation. The higher predisposition of human females to PAH and the use of endothelin blockade in pulmonary arterial hypertension gives this research clinical relevance and biologic importance.