Myocardial Properties of Timothy Syndrome

蒂莫西综合征的心肌特性

• 批准号: 7532150
• 负责人: Randall L. RASMUSSON
• 金额: $ 21.91万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7532150
• 关键词: Adrenergic Agents; Affect; Age; Amino Acids; Arrhythmia; Behavior; Bradycardia; Calcium; Calcium Channel; Cardiac; Case Study; Cell surface; Characteristics; Chemicals; Chimerism; Chronic; Cognitive; Condition; Cyclosporins; Data; Defect; Dihydropyridines; Disease; Disruption; Electrophysiology (science); Exhibits; Exons; Face; Functional disorder; Genetic; Heart; Homeostasis; Human; Immune; Ions; Ketamine; Kinetics; L-Type Calcium Channels; Lead; Learning; Life Expectancy; Link; Localized; Measures; Modeling; Mosaicism; Mus; Muscle Cells; Mutation; Myocardial; Myopia; Numbers; Patients; Phenotype; Phosphorylation; Physiological; Play; Point Mutation; Property; Protein Isoforms; Proteins; Purpose; Rare Diseases; Recovery; Reporting; Research Proposals; Role; Ryanodine Receptor Calcium Release Channel; Side; Surface; Symptoms; Syndactyly; Syndrome; System; Testing; Thinking; Timothy syndrome; Torsades de Pointes; Transgenic Mice; Transgenic Organisms; Transplant Recipients; Ventricular; Ventricular Fibrillation; Ventricular Tachycardia; Work; adrenergic; base; congenital heart disorder; dihydropyridine; gain of function mutation; mouse model; mutant; natural hypothermia; reproductive; voltage

DESCRIPTION (provided by applicant): Disturbances in Ca2+ homeostasis have long been linked to arrhythmias. Timothy Syndrome (TS) is the only cell surface Ca2+ channel defect linked to arrhythmia in humans. A single point mutation on the first S6 domain of Cav1.2 causes the syndrome. On a biophysical level, TS causes the disruption of the voltage dependent component of inactivation in Cav1.2. This slowing of voltage dependent inactivation has been hypothesized to increase net inward current during repolarization thereby prolonging the QT interval in patients. TS is an extremely rare disorder, with less than 30 cases reported. However, recent work has suggested that that a similar kinetic defect in Cav1.2 inactivation can be acquired through chemicals that cause aberrant phosphorylation of the Cav1.2 protein in the same physical region and is predicted to occur in transplant patients undergoing chronic treatment with cyclosporin. Thus, a study of TS may provide an understanding of the general role of Ca2+ channel inactivation in repolarization and promote the understanding of other conditions which alter inactivation of CaV1.2 in heart. Little is known about the actual changes initiated by the TS defect or about the pathophysiology of Timothy syndrome. To better understand this syndrome, we have created a transgenic mouse of TS. This mouse displays QT prolongation. The purpose of this R21 exploratory research proposal is to obtain a characterization of this mouse as a model of the human cardiac TS, particularly with respect to the electrophysiology of calcium channel inactivation, altered calcium handling, changes in other repolarizing currents and the role of Mosaicism/Chimerism. Specific Aim 1: Characterize Calcium Channel Expression and Current Properties This specific aim will characterize basic cardiac properties of the L-type calcium channel in the transgenic TS mouse model. These properties include changes in the magnitude of L-type calcium channel current expression, Cav1.2 activation, inactivation, and recovery as well as the physical distribution of the Cav1.2 isoform. We will also test the pharmacological sensitivity of the TS Cav1.2 mutation to dihydropyridines and beta adrenergic stimulation. Specific Aim 2: Characterize Repolarizing Currents, Calcium Handling and Related Changes. Altered repolarization characteristics in TS mice as measured by QT prolongation are much larger than anticipated on the basis of predicted changes in L-type calcium channel kinetics. This aim will examine whether a parallel reduction in repolarizing currents occurs and examine potential changes in calcium handling mechanisms. Timothy Syndrome is a rare disease resulting from a single well defined genetic defect. Patients with Timothy Syndrome die at an average age of 2.5 years. In order to better understand and treat this disorder we will study a mouse in which the same genetic defect has been artificially introduced.

描述（由申请人提供）：CA2+稳态中的干扰长期与心律不齐有关。蒂莫西综合征（TS）是与人类心律不齐相关的唯一细胞表面Ca2+通道缺陷。 CAV1.2的第一个S6结构域上的单点突变导致综合征。在生物物理水平上，TS导致CAV1.2失活的电压依赖性成分的破坏。假设依赖电压灭活的电压减慢，可以在复极化过程中增加净净电流，从而延长患者的QT间隔。 TS是一种极为罕见的疾病，报告的病例少于30例。然而，最近的工作表明，CAV1.2中的动力学缺陷可以通过化学物质获得，从而导致同一物理区域中CAV1.2蛋白异常磷酸化，并且预计在接受环孢菌素的慢性治疗的移植患者中会发生。因此，对TS的研究可能会理解Ca2+通道失活在复极化中的一般作用，并促进对改变心脏中Cav1.2失活的其他条件的理解。关于TS缺陷或提摩太综合征的病理生理学引发的实际变化知之甚少。为了更好地了解该综合征，我们创建了TS的转基因鼠标。该鼠标显示QT延长。这项R21探索性研究建议的目的是获得该小鼠作为人类心脏TS的模型的表征，尤其是在钙通道失活的电生理学，改变钙处理的情况下，其他复制电流的变化以及镶嵌/嵌合症的作用。特定目标1：表征钙通道表达和当前特性，这种特定目标将表征转基因TS小鼠模型中L型钙通道的基本心脏特性。这些特性包括L型钙通道电流表达，CAV1.2激活，灭活和恢复的大小以及CAV1.2同工型的物理分布的变化。我们还将测试TS CAV1.2突变对二氢吡啶和β肾上腺素能刺激的药理敏感性。特定目标2：表征复制电流，钙处理和相关变化。根据QT延长测量的TS小鼠的复极特性的改变比预期的L型钙通道动力学的变化大得多。该目标将检查复制电流的平行减少并检查钙处理机制的潜在变化。蒂莫西综合征是一种罕见的疾病，是由单个定义的遗传缺陷引起的。蒂莫西综合症的患者平均死亡2.5岁。为了更好地理解和治疗这种疾病，我们将研究一种人为引入相同遗传缺陷的小鼠。