Exploring the role of mitochondria in dysregulated calcium handling in diseased hearts

在美国，心脏病仍然是主要的死亡原因。钙离子释放的改变 肌浆网(SR)由遗传和获得性钙释放通道兰尼定受体缺陷引起 (RyR2)，被认为是一系列破坏性心脏疾病的基础，从心律失常到心脏 失败了。RyR2功能障碍，主要表现为异常活跃(即泄漏)通道，导致异常病例 释放(ACR)。然而，尽管ACR在促进各种疾病状态中的关键作用已经确立，但它 仍然不清楚为什么以及如何相同的潜在缺陷，即异常的钙释放，导致不同的 不同疾病背景下的病理表型。例如，ACR在没有ACR的情况下会导致心律失常 危及生命的儿茶酚胺能多形性室性心动过速的病理重构 遗传性心律失常综合征。相反，ACR与病理性重构和心律失常有关。 糖尿病前期心肌病(Pre-DC)的代谢性疾病模型。这种结果的分歧表明 除了RyR2泄漏外，RyR2钙的异常释放对特定疾病的转化也是至关重要的 然而，对于异常的心肌细胞钙处理之间的联系，人们的认识还存在差距 和心脏病。线粒体感应细胞内钙信号以调节能量产生和细胞 死亡。近年来，SR和线粒体之间的相互作用已成为影响线粒体功能的重要因素。 不同心脏病理的发展。这项研究的初步结果表明，这种相互作用 形成/影响两种不同心脏疾病的病理表型：CPVT和Pre-DC。基座 根据这些结果和文献中的数据，假设SR和SR之间的相互作用 线粒体通过调节/塑造细胞内钙离子参与钙依赖型心脏病的表型 信号。为了验证这一假设，采用新基因的多尺度研究(从分子到整个动物) 小鼠模型的建立及细胞生理学和蛋白质生物化学方法的应用 提出了功能分析方法。这项研究的总体目标是让本科生：1)定义 决定线粒体如何对ACR作出反应的特定方式的分子参与者和因素 在CPVT和DC前环境中塑造细胞内钙动力学并促进心脏病理改变，以及2)利用 直接调节线粒体钙对心肌病理影响的遗传学研究 疾病设置。这项研究具有重要意义，因为它将极大地促进对SR的理解。 线粒体钙信号在CPVT和Pre-DC中的作用，从而促进机制的发展。 这些破坏性心脏病的基础疗法。它还将作为未来翻译的基础 研究为钙依赖型心脏病的亚型提供量身定制的治疗方法。此外，这个项目将 为本科生提供大量参与研究的机会，从而为他们做好充分的准备 与科学或生物医学相关的职业。

Cardiac disease remains the leading cause of death in the United States. Altered Ca release from the sarcoplasmic reticulum (SR) due to genetic and acquired defects in Ca release channels, ryanodine receptors (RyR2s), are thought to underlie a spectrum of devastating cardiac disorders, ranging from arrhythmias to heart failure. RyR2 dysfunction, mainly manifested as an abnormally active (i.e. leaky) channel, leads to aberrant Ca release (ACR). However, while the key role of ACR in contributing to various disease states is established, it remains unclear as to why and how the same underlying defect, i.e. aberrant Ca release, results in different pathological phenotypes in different disease settings. For instance, ACR causes cardiac arrhythmias without pathological remodeling in catecholaminergic polymorphic ventricular tachycardia (CPVT), a life-threatening genetic arrhythmia syndrome. In contrast, ACR is associated with both pathological remodeling and arrhythmias in a metabolic disease model of pre-diabetic cardiomyopathy (pre-DC). This divergence of outcomes suggests that factors in addition to leaky RyR2s are critical for translating aberrant RyR2 Ca release to a particular disease state, however there is a gap in knowledge regarding the connection between abnormal myocyte Ca handling and cardiac disease. Mitochondria sense intracellular Ca signals to mediate energy production and also cell death. Recently, the interplay between SR and mitochondria has emerged as an important factor in the development of different cardiac pathologies. Preliminary results from this study suggest that this interplay shapes/impacts pathological phenotypes in settings of two distinct cardiac diseases: CPVT and pre-DC. Based on these results as well as data in the literature, it is hypothesized that the interplay between SR and mitochondria contributes to Ca-dependent cardiac disease phenotypes by modulating/shaping intracellular Ca signals. To test this hypothesis, multiscale studies (from molecule to whole animal) that employ novel genetic mice models and utilize methods of cellular physiology and protein biochemistry, along with in vivo cardiac functional assays, are proposed. The overall goal of this study is to engage undergraduate students to: 1) define the molecular players and factors that determine the specific manner as to how mitochondria respond to ACR to shape intracellular Ca dynamics and contribute to cardiac pathologies in CPVT vs pre-DC settings, and 2) utilize genetic approaches to explore the effect of directly modulating mitochondria Ca on cardiac pathology in both disease settings. The proposed research is significant because it will greatly advance the understanding of SR- mitochondria Ca signaling in the setting of CPVT and pre-DC, and thus foster the development of mechanism- based therapies for these devastating cardiac diseases. It will also act as a foundation for future translational studies to provide tailored therapies for subtypes of Ca-dependent cardiac disease. Moreover, this project will provide undergraduate students with numerous opportunities to participate in research, thus fully preparing them for scientific or biomedical related careers.