Cell-type Specificity of Heritable Channelopathies: Role of the Purkinje Fiber

遗传性通道病的细胞类型特异性：浦肯野纤维的作用

• 批准号: 8581979
• 负责人: Vivek Iyer
• 金额: $ 13.31万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-19 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8581979
• 关键词: 3-Dimensional; Action Potentials; Affect; American; Arrhythmia; Biological Assay; Biophysics; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular system; Catheters; Cells; Cellular Structures; Cessation of life; Characteristics; Complex; Computer Simulation; Contracts; Electrophysiology (science); Event; Functional disorder; Genes; Genetic; Goals; Grant; Heart; Heart Diseases; Heart failure; Histocompatibility Testing; Human; In Vitro; Induced Mutation; Inherited; Ion Channel; Lead; Lesion; Link; Long QT Syndrome; Maintenance; Medication Management; Membrane Potentials; Modeling; Mus; Muscle; Muscle Cells; Mutation; Myocardial Infarction; Myocardial Ischemia; Myocardium; Organ; Pacemakers; Patch-Clamp Techniques; Patients; Persons; Phenotype; Play; Pluripotent Stem Cells; Potassium Channel; Preparation; Property; Proteins; Regulation; Relative (related person); Reporting; Research; Role; RyR2; Science; Simulate; Sodium Channel; Specificity; Structure of purkinje fibers; System; Technical Expertise; Time; Tissues; Training; Training Programs; Variant; Ventricular; Ventricular Arrhythmia; Ventricular Tachycardia; base; blood pump; career; career development; cell type; design; effective therapy; fiber cell; heart electrical activity; heart function; insight; mouse model; novel; patch clamp; public health relevance; research study; response; simulation; sudden cardiac death

DESCRIPTION (provided by applicant): This proposal details a comprehensive 5-year training program for my career development in cardiovascular research. This plan is designed to provide the additional scientific and technical training that will prepare me for an independent career in academic research. With the support provided by this grant, I will seek additional formal training in ion channel biophysics and the mathematical sciences and further my technical expertise with patch clamp techniques and in vitro analysis of cellular electrophysiology. Sudden cardiac death claims the lives of 350,000 Americans each year (equivalent to 1000 people a day or one person every two minutes). Many of these events occur as a consequence of inherited arrhythmias that cause dysfunction of ion channels, or "channelopathies." The central hypothesis of this proposal is that the cardiac specialized conduction system, comprised of Purkinje fiber (PF) cells, plays a central role in the formation and maintenance of these deadly arrhythmias. In this proposal, the Purkinje system will be studied in a combined in vitro and computational approach in order to examine a novel paradigm: whether differences in tissue type and their interplay modulate the cellular effect of heritable channelopathies. The findings promise to have important implications in the pharmacologic management of affected patients. The insight gained may also enhance our understanding of channel dysfunction in more widespread cardiovascular conditions, such as heart failure and ischemia. My aims are: 1. To investigate how changes in cell type regulate channel dysfunction in single/isolated Purkinje fiber (PF) cells and ventricular myocyte (VM) cells. 2. To study the cellular triggers of arrhythmi in channelopathy using an experimental mouse model, alongside the corresponding computational model. 3. To utilize multidimensional simulation to determine the impact of mutations in the Purkinje fiber system and interplay with the ventricle, establishing a link between genetic lesion and arrhythmia on the whole organ level.

描述(由申请者提供)：这份建议书详细说明了我在心血管研究领域的职业发展的5年综合培训计划。这项计划旨在提供额外的科学和技术培训，为我在学术研究领域的独立生涯做好准备。在这笔赠款的支持下，我将寻求更多的离子通道生物物理学和数学科学方面的正式培训，并进一步发展我在膜片钳技术和细胞电生理学体外分析方面的技术专长。心脏性猝死每年夺走35万美国人的生命(相当于每天1000人或每两分钟一人)。这些事件中的许多都是遗传性心律失常的结果，这种心律失常会导致离子通道功能障碍，或称为“通道病”。这一建议的中心假设是，由浦肯野纤维(PF)细胞组成的心脏专门传导系统在这些致命心律失常的形成和维持中发挥着核心作用。在这项提议中，浦肯野系统将在体外和计算相结合的方法中进行研究，以检验一种新的范式：组织类型的差异及其相互作用是否调节可遗传通道病的细胞效应。这一发现有望对受影响患者的药理学管理具有重要意义。获得的洞察力也可能增强我们对更广泛的心血管疾病，如心力衰竭和缺血的通道功能障碍的理解。我的目标是：1.研究细胞类型的改变如何调节单个/分离的浦肯野纤维(PF)细胞和心室肌细胞(Vm)的通道功能障碍。2.利用实验小鼠模型，结合相应的计算模型，研究经络病心律失常的细胞触发机制。3.利用多维模拟来确定浦肯野纤维系统突变的影响以及与心室的相互作用，在整个器官水平上建立遗传损害与心律失常之间的联系。