Gender differences and endothelin responses in right ventricular afterload stress

简介(申请人提供)：本建议旨在培养安娜·赫姆尼斯博士的科学发展能力，提高她的研究技能，使她成为一名独立的调查人员。赫姆尼斯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。威斯康星大学通过其众多的实验室资源、教育机会和专家教师队伍，为培养内科科学家提供了有利的环境。在约翰·纽曼博士的指导下，海恩斯博士将设计和进行实验，以增强她在右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方面的专业知识。这些技能将为赫姆内斯博士在右室研究领域追求独立的学术生涯奠定基础。右室(RV)应激反应是晚期肺动脉高压患者生存的主要决定因素，但由于非标准的肺血管阻塞导致右室应激，研究甚少。我们通过结扎主肺动脉建立了右室肥大模型。在初步数据中，我们提出的证据表明，RV后负荷应激反应是性别相关的，性别改变了RV对内皮素拮抗的反应。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，产生对后负荷应激的形态、生理和生化RV反应，这在男性和女性中是不同的。为了验证这一假说，我们制定了以下具体目标：1)在此背景下，确定性激素对后负荷诱导的RV肥大的影响和对RV心肌细胞内皮素信号的影响；2)确定内皮素对后负荷应激RV和心肌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。房车对后负荷应激反应的性别差异需要进一步的探讨和解释。人类女性对PAH的易感性较高，在肺动脉高压中使用内皮素阻滞剂使这项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.