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.

项目摘要/摘要 在心肌细胞兴奋（ECC）和CA从肌浆网（SR）中释放 具有由于缺乏或不规则组织的横向小管膜而产生的独特特征 系统。心肌细胞具有两种类型的SR，连接（J-SR）和非界面（NJ-SR）。 CA从J-释放 SR通过电压门控L型CA通道（ICA，L）控制CA，而从NJ-SR释放 随后通过新鉴定的“火 - 弥漫性摄取火力（FDUF）机制。 IP3受体诱导的CA释放（IICR）对ECC有助于 增强肌力，但也导致心律失常CA释放和替代品。心脏替代品一直是 与心律不齐有关，包括心房颤动。在 动作电位（AP）持续时间（APD，电气替代品），收缩强度和CA瞬态（CAT） 振幅，从而产生动态心律失常底物。双向耦合的干扰 [CA] I和膜电压（VM）调节（[Ca]I↔VM耦合）的构成负责发生的交替。 心脏结构和电性能的性别差异与心律不齐的差异有关 敏感性并确定替代性诱导性。关注FDUF机制，总体目标是 建立心房ECC，CA释放和心房替代品及其性别特异性属性的机械模型 细胞，细胞对和器官水平。 具体目标1。确定房屋替代品的FDUF依赖性机制。我们将确定关键 新型FDUF范式在心房替代品中的作用，检验了1）脱离J-SR和NJ-的假设 SR CA版本促进了“反向” FDUF，并触发了替代方案； 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 以及氧化还原信号传导和5）IICR调节FDUF和替代品。 具体目标2。确定细胞对中的FDUF替代机制。替代品是VM或CA驱动。 VM驱动的替代品在空间上是均匀的，而CA驱动的替代品在空间上可能是不一致的。 在短距离区域的替代区域外。细胞对定义基本结构和功能 细胞电池通信的单位。我们将测试1）CAT和APD替代品的时空组织 细胞对，2）在CA驱动的交替物中如何使用FDUF机构，SERCA，线粒体信号和IICR 确定细胞对替代品； 3）VM驱动的替代品如何在相邻细胞中沉淀猫替代品。 特定目的3。确定CA-和VM驱动的时空组织和机制 组织替代品。我们将在器官一级（灌注心脏，活动物）确定机制， 1）CA驱动的表现和时空组织和2）电压驱动的替代品，并测试 减少促疾病替代品的药理干预措施。