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安娜赫姆内斯博士的科学发展和提高其研究技能，使其成为一名独立的研究者。Hemnes博士目前正在范德比尔特大学医学中心（VUMC）的肺部研究中心发展她的学术生涯。VUMC通过其许多实验室资源，教育机会和专家教师提供了一个有利于发展医生科学家的环境。在John纽曼博士的指导下，Hemnes博士将设计和执行实验，以提高她在右心室对后负荷应激反应的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的课程，她将获得在实验设计和执行，转基因小鼠模型的使用，细胞和分子生物学技术，统计分析和数据报告的专业知识。这些技能将为Hemnes博士在右心室研究中追求独立的学术生涯奠定基础。右心室（RV）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，因此研究较少。我们通过结扎主肺动脉建立了右心室肥大模型。在初步的数据中，我们提出的证据表明，RV后负荷应激反应是性别依赖性的，性别改变RV对内皮素拮抗作用的反应。我们假设，雌激素是保护性的RV反应后负荷压力和内皮素和性激素相互作用，产生形态，生理和生化RV反应后负荷压力是不同的男性和女性。为了验证这一假设，我们开发了以下具体目标：1）确定性激素对后负荷诱导的RV肥大的影响，并在此背景下改变RV心肌细胞中的内皮素信号; 2）确定内皮素对后负荷应激的RV和心肌细胞内的细胞内雌激素信号的影响。RV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需要进一步探讨和解释。人类女性更易患PAH和在肺动脉高压中使用内皮素阻滞剂，这使得本研究具有临床相关性和生物学重要性。

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.