Modeling the spatiotemporal properties of crosstalk between RYR-mediated and IP3R-mediated calcium signaling in cardiac myocytes

模拟心肌细胞中 RYR 介导和 IP3R 介导的钙信号传导之间串扰的时空特性

• 批准号: 10701689
• 负责人: DeAnalisa Jones
• 金额: $ 4.9万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701689
• 关键词: Address; Affect; Arrhythmia; Behavior; Calcium; Calcium Signaling; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cell membrane; Cell physiology; Cells; Cessation of life; Clinical; Computer Models; Coupling; Cytoplasm; Data; Development; Disease; Event; Foundations; Frequencies; Geometry; Heart Atrium; Heart failure; Heterogeneity; In Vitro; Individual; Link; Measures; Mediating; Membrane; Minor; Modeling; Muscle Cells; Outcome Measure; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Play; Probability; Process; Property; Rattus; Risk; Role; Ryanodine Receptor Calcium Release Channel; Signal Transduction; Site; Sum; Testing; Training; Validation; Ventricular; Ventricular Arrhythmia; Visualization; cell type; design; insight; mathematical model; multi-scale modeling; nanometer; novel; predictive modeling; prevent; receptor; receptor expression; spatiotemporal; sudden cardiac death; tool; voltage

PROJECT SUMMARY Sudden cardiac death (SCD) is estimated to cause 4-5 million deaths per year worldwide. In patients with heart failure, SCD is the number one leading cause of death and is linked to the onset of ventricular arrhythmias. Understanding how ventricular arrhythmias arise in patients with heart failure is thus critical to designing effective drugs that prevent SCD and prolong survival in patients with heart failure. In ventricular cardiomyocytes, the foundation of excitation-contraction coupling is intracellular Ca2+ signaling. Specifically, activation of voltage-gated Ca2+ channels cause Ca2+ release from the SR via Ca2+ release channels resulting in local increases in cytoplasmic [Ca2+] known as “sparks.” Sparks then sum to generate global increases in cytoplasmic [Ca2+] across the cell called Ca2+ transients. Under normal circumstances, this is a tightly controlled and coordinated process that leads to synchronous contraction of the ventricles. When disturbed, however, dyssynchronous Ca2+ release across the cell, known as Ca2+ waves, can lead to uncoordinated ventricular contraction i.e. arrhythmia. When studying conditions that are technically challenging—such as visualizing the arrangement of individual Ca2+ release channels on the SR—or investigating conditions that cannot be easily manipulated—such as studying how changing that arrangement affects probability of arrhythmogenic wave formation—computational modeling becomes very useful. Such variables can be easily manipulated to predict experimentally measurable outcomes. While modeling has been used to study Ca2+ sparks and waves previously, current mathematical models make several assumptions about the subcellular properties of Ca2+ release units. More specifically, they assume that only ryanodine receptors are responsible for SR Ca2+ release while ignoring IP3 receptors, which are lowly expressed in healthy ventricular myocytes and show increased expression in failing myocytes. They also assume homogeneous dyadic geometry and spatial arrangement of channels between release sites. While it is known that properties such as the number of release channels in a release unit are variable in healthy myocytes, these effects as well as changes to dyadic geometry become especially prominent in failing ventricular myocytes in which remodeling has occurred, and should thus be included in models. Given the immense clinical need to understand how changes to ventricular myocytes in heart failure predisposes to arrhythmia and SCD yet the difficulty in experimentally manipulating important spatial and geometric changes found in failing myocytes, there is a clear need for accurate mathematical models of intracellular Ca2+ signaling in failing compared to healthy myocytes. I plan to address this need by developing more accurate models of Ca2+ sparks and Ca2+ waves that account for (1) heterogeneity in Ca2+ release units and (2) the expression of IP3 receptors in both healthy and diseased ventricular myocytes. I will then refine these models based on in vitro experimental findings.

项目概要 据估计，全球每年有 4-500 万人死于心源性猝死 (SCD)。对于心脏病患者 心律失常是导致死亡的第一大原因，并且与室性心律失常的发生有关。 因此，了解心力衰竭患者如何发生室性心律失常对于设计至关重要 预防 SCD 并延长心力衰竭患者生存期的有效药物。心室内 心肌细胞中，兴奋-收缩耦合的基础是细胞内 Ca2+ 信号传导。具体来说， 电压门控 Ca2+ 通道的激活导致 Ca2+ 通过 Ca2+ 释放通道从 SR 释放，从而导致 细胞质 [Ca2+] 的局部增加被称为“火花”。然后火花相加，产生全球增长 细胞质 [Ca2+] 穿过细胞称为 Ca2+ 瞬变。在正常情况下，这是一个紧密的 导致心室同步收缩的受控和协调过程。当受到打扰时， 然而，跨细胞的不同步 Ca2+ 释放（称为 Ca2+ 波）可能会导致不协调 心室收缩，即心律失常。 当研究技术上具有挑战性的条件时，例如可视化个体的排列 SR 上的 Ca2+ 释放通道 - 或调查不易操纵的条件 - 例如 研究改变这种排列如何影响致心律失常波形成的概率——计算 建模变得非常有用。这些变量可以很容易地操纵来预测实验可测量的结果 结果。虽然以前已使用建模来研究 Ca2+ 火花和波，但当前的数学 模型对 Ca2+ 释放单位的亚细胞特性做出了一些假设。更具体地说， 他们假设只有兰尼碱受体负责 SR Ca2+ 的释放，而忽略了 IP3 受体， 它们在健康的心室肌细胞中表达较低，而在衰竭的心肌细胞中表达增加。 他们还假设释放点之间的通道具有均匀的二元几何形状和空间排列。 虽然众所周知，诸如释放单元中释放通道的数量之类的属性是可变的 对于健康的肌细胞来说，这些影响以及二元几何形状的变化在失败时变得尤为突出 发生重构的心室肌细胞，因此应包含在模型中。 鉴于临床迫切需要了解心力衰竭中心室肌细胞的变化 易导致心律失常和 SCD，但在实验上操纵重要的空间和 在衰竭的心肌细胞中发现几何变化，显然需要精确的数学模型 与健康肌细胞相比，细胞内 Ca2+ 信号传导失败。我计划通过开发来解决这个需求 更准确的 Ca2+ 火花和 Ca2+ 波模型解释了 (1) Ca2+ 释放单元的异质性 (2)IP3受体在健康和患病心室肌细胞中的表达。然后我会完善 这些模型基于体外实验结果。