The Role of Cardiac Caveolae in Healthy and Diseased Hearts

小泡是细胞膜上小的欧米伽形状的内陷。它们被认为是调节心脏活动以应对压力的关键。本研究旨在探讨腔泡电流对心脏电生理的影响。在心肌细胞中，已知小泡含有离子通道，它们的颈部可以在肾上腺素能刺激下打开或关闭。在开放结构中，腔泡颈形成通向细胞外空间的低阻力通道，从而为膜提供额外的离子通道。然而，在封闭构型中，小泡及其离子通道与质膜和细胞外空间隔离。小泡在心肌细胞中普遍存在（每个细胞大约20,000-25,000个），使用β激动剂可触发小泡颈部的开放，导致钠电流增加高达40%。这种腔泡电流被纳入心脏电生理学的数学模型，以解决三个基本问题。首先，小泡在健康心脏中的作用是什么？回答这个问题需要用包括腔泡电流在内的心室肌细胞的生物物理详细模型进行模拟。研究了单动作电位和周期性组织的变化。分析（主要是动力系统，分岔和渐近）一个更易于处理的简化模型也被用来理解结果。其次，在封闭构型中，微泡的行为是什么？其基本思想是，封闭小泡内的通道暴露在不同的电压和不同的离子浓度下。因此，这些通道与外膜上的通道处于不同的状态，当小泡打开时，它们的行为也不同。由于每个小泡只有少量的通道，并且由于小泡非常小，单个离子穿过膜的运动会产生显著的电压变化，因此使用了连续确定性和离散随机模型的组合。第三，结构蛋白小窝蛋白-3的突变如何导致动作电位和心律失常的变化？研究人员假设，小泡蛋白-3突变可导致小泡颈部打开和关闭动力学的变化，并且在某些情况下，颈部可以更快地打开和关闭，因此单个小泡可能在单个动作电位内改变一次或多次状态。使用概率密度方法，其中微泡的状态密度演变。小窝蛋白-3的改变可引起许多小窝病，如肌肉萎缩症、高血凝症、肌病、长QT综合征（特别是LQTS9）和婴儿猝死综合征（lqts3样）。因此，小脑泡被认为在心脏电活动的调节中起着关键作用。然而，它们的作用尚未被纳入现有的心脏模型。这个项目是第一个模拟小泡调节作用的项目。初步结果表明，加入小泡动力学可以对心脏动作电位产生戏剧性和意想不到的影响。这是小泡研究的一个范式转变，因为到目前为止，工作主要集中在小泡在信号传导中的作用，而不是它们对电生理的影响。本研究的长期目标是了解小泡作为健康人肾上腺素能反应的一部分的作用，并研究与小泡突变相关的各种病理。

Caveolae are small omega shaped invaginations in the cell membrane. They are believed to be crucial in the regulation of cardiac activity in response to stress. The purpose of this project is to investigate the effects of caveolar currents on cardiac electrophysiology. In cardiac myocytes, caveolae are known to contain ion channels and their necks can be open or closed in response to adrenergic stimulation. In the open configuration, the caveolar necks create a low resistance pathway to the extracellular space thus presenting additional ion channels to the membrane. However, in the closed configuration, the caveolae and their ion channels are isolated from the plasma membrane and extracellular space. Caveolae are ubiquitous in cardiac myocytes (roughly 20,000-25,000 per cell) and application of a beta agonist has been shown trigger the opening of caveolar necks leading to an increase in sodium current of up to 40%. This caveolar current is incorporated into mathematical models of cardiac electrophysiology in order to address three fundamental questions. First, what is the role of caveolae in healthy heart? Answering this question requires simulations with a biophysically detailed model of the ventricular myocyte which includes the caveolar current. Changes in both single action potentials and periodically paced tissue are explored. Analysis (primarily dynamical systems, bifurcations and asymptotics) of a more tractable reduced model is also used to understand the results. Second, what is the behavior of caveolae in the closed configuration? The fundamental idea is that the channels inside a closed caveolae are exposed to a different voltage and different ionic concentration. These channels will therefore be in a different state than those on the exterior membrane and will behave differently when the caveolae opens. Because there are only a small number of channels per caveolae and because the caveolae are so small that the movement of a single ion across the membrane creates a significant change in voltage, a combination of continuum-deterministic and discrete-stochastic modeling is used. Third, how do mutations in the structural protein caveolin-3 lead to changes in the action potential and arrhythmias? The investigators hypothesize that caveolin-3 mutations can lead to changes in the opening and closing dynamics of the caveolar neck and that in some cases the neck can flicker open and close more quickly so that a single caveolae may change state one or more times within a single action potential. A probability density approach is used in which the density of states of the caveolae evolves.Changes in the primary structural protein for caveolae, known as caveolin-3 can cause a host of caveolinopathies such as muscular dystrophy, hyperCKemia, myopathy, long QT syndrome (specifically LQTS9) and sudden infant death syndrome (LQTS3-like). Caveolae are therefore believed to play a key role in the regulation of cardiac electrical activity. However, their effect has not yet been incorporated into existing cardiac models. This project is among the first to model the regulatory effects of caveolae. Preliminary results show that including the dynamics of caveolae can have dramatic and unexpected effects on the cardiac action potential. This is a paradigm shift in caveolar research since the work up to this point has focused on the role of caveolae in signaling rather than their effects on electrophysiology. The long term goal of this research is to understand the role of caveolae as part of the healthy human adrenergic response and to investigate the various pathologies associated with caveolar mutations.