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）：本提案是针对 R21 申请的 RFA 的修订申请，旨在推进女性健康研究中的新科学。尽管心脏病是美国男性和女性的第一大杀手，但心脏病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），人们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患药物引起的心律失常，人们知之甚少。 该应用旨在通过确定心脏中两种主要复极电流 IKr 和 IK 的性依赖性和激素调节的分子基础来推进女性健康研究的科学。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是造成心脏复极性别差异的原因。这与当前的概念背道而驰，即动作电位持续时间纯粹是心律失常易感性的关键决定因素。我们提出，重要的因素不是绝对动作电位长度，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 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是由 KCNE 辅助亚基的存在决定的。我们的假设是，这些亚基的激素调节是决定男性和女性肌细胞之间差异的主要因素。我们将通过确定来自雄性和雌性皮肤细胞诱导多能干细胞 (iPSC) 的人类心肌细胞，以及来自雄性、雌性和卵巢切除 (OVX) 豚鼠的心室肌细胞的 IKr 和 IKs 电生理特征来检验这一假设。我们还将让肌细胞接触雌二醇和睾酮，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。我们将利用实验数据开发人类和豚鼠动作电位的数学模型，其中包含 IKr 和 IK 的激素调节。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），这些行为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测试的假设，这些假设很容易应用于人类的电生理学研究。

项目成果

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

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