Sex Differences in Molecular Heterogeneity of Cardiac Repolarization

心脏复极分子异质性的性别差异

• 批准号: 8191320
• 负责人: GLENNA C L BETT
• 金额: $ 23.12万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8191320
• 关键词: Action Potentials; Animals; Area; Arrhythmia; Basic Science; Behavior; Cardiac; Cardiac Myocytes; Cavia; Cells; Clinical; Clinical Trials; Complex; Data; Dependence; Electrophysiology (science); Estradiol; Female; Genomics; Goals; Health; Healthcare; Heart; Heart Diseases; Heterogeneity; Hormonal; Hormones; Human; Intervention; Kinetics; Length; Long QT Syndrome; Messenger RNA; Modeling; Molecular; Molecular Biology; Morphology; Muscle Cells; Mutation; Nature; Outcome; Participant; Patients; Pharmaceutical Preparations; Predisposition; Process; Proteins; Relative (related person); Research; Risk; Role; Safe Sex; Science; Screening procedure; Sex Characteristics; Skin; Small Interfering RNA; Specificity; System; Testing; Testosterone; Time; Torsades de Pointes; Ventricular; Woman; Women' s Health; base; hormone regulation; human female; improved; induced pluripotent stem cell; innovation; mRNA Expression; male; mathematical model; men; mutant; novel; research study; response; sex; simulation; therapeutic target; voltage clamp

DESCRIPTION (provided by applicant): This proposal is a revised application in response to an RFA for R21 applications to advance Novel Science in Women's Health Research. Although heart disease is the #1 killer of both Men and Women in the US, only 27% of participants in cardiac clinical trials are women. In basic research, most experiments are performed on male animals only. It is therefore not surprising that little is known about the basic molecular mechanisms even for such clinically important fundamental factors such as why female cardiac action potentials are longer than male action potentials. Even less is known about why 70% of congenital Long QT syndrome patients are women, and why women are at particular risk for drug induced arrhythmias. This application proposes to advance science in women's health research by determining the molecular basis for sex dependence and hormonal regulation of IKr and IKs, the two major repolarizing currents in heart. This research is strongly hypothesis driven, and the overall guiding hypothesis is that differences in the electrophysiological and pharmacological profile of IKr and IKs are responsible for sex differences in cardiac repolarization. This is a departure from the current concept that it is purely the action potential duration that is the key determinant of arrhythmia susceptibility. We are proposing that the important factor is not the absolute action potential length, but the relative contribution of IKr and IKs, combined with their pharmacological sensitivities that are a critical factor in arrhythmogenesis. The alpha subunits of IKr and IKs are HERG and KCNQ1 respectively. However, their relative expression, electrophysiological and pharmacological profiles are determined by the presence of KCNE ancillary subunits. Our hypothesis is that hormonal regulation of these subunits is the major factor in determining differences between male and female myocytes. We will test this hypothesis by determining IKr and IKs electrophysiological profile in human cardiomyocytes derived from male and female induced Pluripotent Stem Cells (iPSCs) from skin cells, as well as ventricular myocytes from male, female and ovariectomized (OVX) guinea pigs. We will also expose myocytes to estradiol and testosterone to test the direct effects of hormones on currents and use molecular interventions to determine subunit specificity. We will use the experimental data to develop mathematical models of human and guinea-pig action potentials which contain hormonal regulation of IKr and IKs. We will use these models to make predictions about the dynamic behavior of repolarization (e.g., restitution, QT prolongation and pharmacological sensitivity) which can be tested in our experimental human and guinea pig models. These innovative simulation studies will provide testable hypotheses which are readily applicable to electrophysiological studies in humans. PUBLIC HEALTH RELEVANCE: This proposal seeks to understand the basis of sex-differences in the electrical activity and pharmacological sensitivity of the heart. Sex is an often overlooked fundamental clinical variable, which can have a significant impact on health outcome. Understanding the basis of cardiac sex differences offers the opportunity for translational advances in the identification of therapeutic targets with the potential to improve patient outcomes and improve healthcare for both men and women.

描述（由申请人提供）：本提案是一份修订后的申请，旨在响应R21申请的RFA，以推进女性健康研究中的新科学。虽然心脏病是美国男性和女性的头号杀手，但心脏临床试验的参与者中只有27%是女性。在基础研究中，大多数实验仅在雄性动物身上进行。因此，即使对于临床上重要的基本因素，例如为什么女性心脏动作电位比男性动作电位长，对基本分子机制知之甚少也就不足为奇了。关于为什么70%的先天性长QT综合征患者是女性，以及为什么女性特别容易发生药物诱导的心律失常，我们所知甚少。 该申请提出通过确定IKr和IKs（心脏中的两个主要复极化电流）的性依赖和激素调节的分子基础来推进女性健康研究中的科学。这项研究是强烈的假设驱动，总体指导假设是，IKr和IKs的电生理和药理学特征的差异是心脏复极的性别差异的原因。这与当前的概念不同，即单纯的动作电位时程是心律失常易感性的关键决定因素。我们认为，重要的因素不是绝对的动作电位长度，而是IKr和IKs的相对贡献，以及它们的药理学敏感性，这是一个关键因素。 IKr和IKs的α亚基分别是HERG和KCNQ1。然而，它们的相对表达，电生理学和药理学特征由KCNE辅助亚基的存在决定。我们的假设是，这些亚基的激素调节是决定男性和女性心肌细胞之间差异的主要因素。我们将通过测定来自皮肤细胞的雄性和雌性诱导多能干细胞（iPSC）的人心肌细胞以及来自雄性、雌性和卵巢切除（OVX）豚鼠的心室肌细胞中的IKr和IKs电生理特征来检验这一假设。我们也将暴露于雌二醇和睾酮的心肌细胞，以测试激素对电流的直接影响，并使用分子干预来确定亚基特异性。我们将使用实验数据来开发包含IKr和IKs的激素调节的人类和豚鼠动作电位的数学模型。我们将使用这些模型来预测复极的动态行为（例如，恢复、QT延长和药理学敏感性），其可以在我们的实验人类和豚鼠模型中进行测试。这些创新的模拟研究将提供可检验的假设，这些假设很容易适用于人类的电生理研究。 公共卫生关系：该提案旨在了解心脏电活动和药理学敏感性的性别差异的基础。性别是一个经常被忽视的基本临床变量，它可能对健康结果产生重大影响。了解心脏性别差异的基础为识别治疗靶点提供了转化进展的机会，这些靶点有可能改善患者结局并改善男性和女性的医疗保健。