Atrial Excitation-Contraction Coupling, Calcium Signaling and Electro-Mechanical Alternans

心房兴奋-收缩耦合、钙信号传导和机电交替

• 批准号: 10667610
• 负责人: LOTHAR A BLATTER
• 金额: $ 70.68万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-20 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667610
• 关键词: Action Potentials; Affect; Anesthesia procedures; Animal Testing; Animals; Arrhythmia; Atrial Fibrillation; Attenuated; Buffers; Calcium Signaling; Cardiac; Cell Communication; Cells; Complex; Coupling; Dependence; Development; Diffuse; Electrophysiology (science); Endowment; Fire - disasters; Gap Junctions; Generations; Goals; Heart; Heart Atrium; Heterogeneity; ITPR1 gene; Individual; Intervention; Ion Channel; Link; Membrane; Mitochondria; Modeling; Morphology; Muscle Cells; Organ; Oxidation-Reduction; Perfusion; Peripheral; Phase; Predisposition; Property; Protocols documentation; Reactive Oxygen Species; Regional Perfusion; Regulation; Risk; Risk Factors; Role; Sarcoplasmic Reticulum; Sex Differences; Signal Transduction; Source; System; Testing; Therapeutic Intervention; Tissues; electrical property; experimental study; in vivo; novel; pharmacologic; receptor; sex; spatiotemporal; sudden cardiac death; uptake; voltage; voltage clamp

PROJECT SUMMARY/ABSTRACT In atrial myocytes excitation-contraction coupling (ECC) and Ca release from the sarcoplasmic reticulum (SR) have unique features that result from the lack or the irregular organization of the transverse tubule membrane system. Atrial myocytes have two types of SR, junctional (j-SR) and non-junctional (nj-SR). Ca release from j- SR is controlled by Ca entry through voltage-gated L-type Ca channels (ICa,L) whereas release from nj-SR occurs by subsequent propagating wave-like Ca-induced Ca release (CICR) driven by the newly identified 'fire- diffuse-uptake-fire' (FDUF) mechanism. IP3 receptor-induced Ca release (IICR) contributes to ECC by enhancing inotropy, but also leads to arrhythmogenic Ca release and alternans. Cardiac alternans has been linked to cardiac arrhythmia, including atrial fibrillation. Alternans is defined as beat-to-beat alternations in action potential (AP) duration (APD, electrical alternans), contraction strength and Ca transient (CaT) amplitude, and thereby generates a dynamic arrhythmia substrate. Disturbances of the bi-directional coupling of [Ca]i and membrane voltage (Vm) regulation ([Ca]i↔Vm coupling) are responsible for alternans occurrence. Sex differences in cardiac structural and electrical properties have been linked to differences in arrhythmia susceptibility and determine alternans inducibility. Focusing on the FDUF mechanism, the overall goals are to establish a mechanistic model of atrial ECC, Ca release and atrial alternans and its sex-specific attributes at cellular, cell pair and organ level. Specific aim 1. Determine FDUF-dependent mechanisms of atrial alternans. We will determine the critical role of the novel FDUF paradigm in atrial alternans, testing the hypotheses that 1) uncoupling of j-SR and nj- SR Ca release promotes 'reverse' FDUF and triggers alternans; 2) the FDUF trigger signal (ICa,L, junctional CaT) has Vm dependence, and that 3) SERCA dependent Ca uptake; 4) mitochondrial Ca buffering, energetics and redox signaling and 5) IICR modulate FDUF and alternans. Specific aim 2. Determine FDUF alternans mechanisms in cell pairs. Alternans is either Vm- or Ca-driven. Vm-driven alternans is spatially homogeneous, while Ca-driven alternans can be spatially discordant where over short distances regions alternate out-of-phase. Cell pairs define the elementary structural and functional unit of cell-cell communication. We will test 1) the spatio-temporal organization of CaT and APD alternans in cell pairs, 2) how during Ca-driven alternans the FDUF mechanism, SERCA, mitochondrial signaling and IICR determine cell pair alternans; and 3) how Vm-driven alternans precipitates CaT alternans in adjacent cells. Specific aim 3. Determine the spatio-temporal organization and mechanisms of Ca- and Vm-driven tissue alternans. We will determine at organ level (perfused hearts, live animals) the mechanisms, manifestations and spatio-temporal organization of 1) Ca-driven and 2) voltage-driven alternans, and test pharmacological interventions to reduce pro-arrhythmic alternans risk.

项目概要/摘要 心房肌细胞兴奋-收缩耦合 (ECC) 和肌浆网 (SR) 中的 Ca 释放 由于横管膜缺乏或组织不规则而具有独特的特征 心房肌细胞有两种类型的 SR，即连接型 (j-SR) 和非连接型 (nj-SR)。 SR 受 Ca 通过电压门控 L 型 Ca 通道 (ICa,L) 的进入控制，而从 nj-SR 释放 由新发现的“火-诱导钙释放”（CICR）驱动的后续传播波状钙诱导钙释放（CICR）发生 扩散吸收火”（FDUF）机制通过IP3受体诱导的Ca释放（IICR）促进ECC。 增强正性肌力，但也会导致心律失常的 Ca 释放和心脏交替。 与心律失常相关，包括心房颤动，其定义为逐次心跳交替。 动作电位 (AP) 持续时间（APD，电交替）、收缩强度和 Ca 瞬态 (CaT) 幅度，从而产生双向耦合的动态心律失常基质。 [Ca]i 和膜电压 (Vm) 调节（[Ca]i↔Vm 耦合）是交替发生的原因。 心脏结构和电特性的性别差异与心律失常的差异有关 易感性并确定交替糖诱导性 重点关注 FDUF 机制，总体目标是 建立心房 ECC、Ca 释放和心房交替的机制模型及其性别特异性属性 细胞、细胞对和器官水平。 具体目标 1. 确定心房交替的 FDUF 依赖性机制 我们将确定关键的心房交替机制。 新型 FDUF 范式在心房交替中的作用，测试以下假设：1) j-SR 和 nj- 解偶联 SR Ca 释放促进“反向”FDUF 并触发交替 2) FDUF 触发信号（ICa、L、连接）； CaT) 具有 Vm 依赖性，并且 3) SERCA 依赖性 Ca 摄取 4) 线粒体 Ca 缓冲、能量学； 和氧化还原信号传导，5) IICR 调节 FDUF 和交替糖。 具体目标 2. 确定细胞对中的 FDUF 交替机制是 Vm 驱动的还是 Ca 驱动的。 Vm 驱动的交替在空间上是均匀的，而 Ca 驱动的交替可能在空间上不一致，其中 在短距离内，区域异相交替，定义了基本的结构和功能。 我们将测试 1）CaT 和 APD 交替的时空组织。 细胞对，2) 在 Ca 驱动的交替过程中，FDUF 机制、SERCA、线粒体信号传导和 IICR 是如何进行的 确定细胞对交替蛋白；3) Vm 驱动的交替蛋白如何在相邻细胞中沉淀 CaT 交替蛋白。 具体目标3.确定Ca和Vm驱动的时空组织和机制 我们将在器官水平（灌注心脏、活体动物）确定机制， 1) Ca 驱动和 2) 电压驱动交替的表现和时空组织，以及测试 药物干预以降低促心律失常交替风险。