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: 8301537
• 负责人: GLENNA C L BETT
• 金额: $ 19.81万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8301537
• 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.

描述（由申请人提供）：该提案是对RFA的R21应用程序的修订申请，以推动妇女健康研究中的新科学。尽管心脏病是美国男性和女性的杀手，但只有27％的心脏临床试验参与者是女性。在基础研究中，大多数实验仅对雄性动物进行。因此，即使对于如此重要​​的基本因素（例如为什么女性心脏动作电位）比男性动作电位更长的基本分子机制，对于基本的分子机制知之甚少，这并不奇怪。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有药物引起心律不齐的风险，甚至更少知道。 该应用建议通过确定IKR和IKS的性别依赖性和激素调节的分子基础来推进妇女健康研究中的科学，这是心脏中两个主要的重极化电流。这项研究是强烈的假设驱动的，总体指导假设是，IKR和IK的电生理学和药理学特征的差异负责心脏复极化的性别差异。这与当前的概念背道而驰，即纯粹是动作潜在持续时间，这是心律不齐敏感性的关键决定因素。我们提出，重要因素不是绝对作用的潜在长度，而是IKR和IK的相对贡献，以及它们的药理敏感性，这是心律失常发生的关键因素。 IKR和IK的α亚基分别为HERG和KCNQ1。但是，它们的相对表达，电生理和药理特征取决于KCNE辅助亚基的存在。我们的假设是，这些亚基的荷尔蒙调节是确定雄性和雌性心肌差异的主要因素。我们将通过确定源自皮肤细胞的男性和女性诱导多能干细胞（IPSC）的人类心肌细胞中的IKR和IKS电生理学特征来检验这一假设，以及来自皮肤细胞的多能干细胞（IPSC），以及来自雄性，雌性和卵巢的室性肌细胞（雌性和卵巢）的肌细胞。我们还将将心肌细胞暴露于雌二醇和睾丸激素中，以测试激素对电流的直接影响，并使用分子干预措施来确定亚基特异性。我们将使用实验数据来开发包含IKR和IKS激素调节的人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化的动态行为（例如，恢复，QT延长和药理学敏感性），可以在我们的实验性人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。

项目成果

Sex specific association of potassium channel subunits.

钾通道亚基的性别特异性关联。

• DOI: 10.1113/jphysiol.2011.221630
• 发表时间: 2011
• 期刊: The Journal of physiology
• 作者: Duffey,MichaelE;Bett,GlennaCL
• 通讯作者: Bett,GlennaCL

Interaction of the S6 proline hinge with N-type and C-type inactivation in Kv1.4 channels.

S6 脯氨酸铰链与 Kv1.4 通道中 N 型和 C 型失活的相互作用。

• DOI: 10.1016/j.bpj.2012.08.036
• 发表时间: 2012
• 期刊: Biophysical journal
• 影响因子: 3.4
• 作者: Bett,GlennaCL;Lis,Agnieszka;Guo,Hong;Liu,MiMi;Zhou,Qinlian;Rasmusson,RandallL
• 通讯作者: Rasmusson,RandallL