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

心脏病仍然是美国的主要死亡原因。改变了钙的释放 肌浆网（SR）由于遗传和获得性缺陷的钙释放通道，兰尼碱受体 （RyR 2），被认为是一系列破坏性心脏疾病的基础，从心律失常到心脏病， 失败RyR 2功能障碍，主要表现为异常活性（即渗漏）通道，导致异常Ca 释放（ACR）。然而，虽然ACR在促成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，即异常钙释放，导致不同的 不同疾病背景下的病理表型。例如，ACR引起心律失常， 儿茶酚胺能多形性室性心动过速（CPVT）的病理性重构， 遗传性心律失常综合征相反，ACR与病理性重构和心律失常相关 在糖尿病前期心肌病（pre-DC）代谢疾病模型中。这种结果的差异表明， 除了RyR 2渗漏外，其他因素对于将异常RyR 2 Ca释放转化为特定疾病至关重要， 然而，关于异常肌细胞钙处理之间的联系， 和心脏病。线粒体感知细胞内Ca信号以介导能量产生， 死亡最近，SR和线粒体之间的相互作用已经成为一个重要的因素， 不同心脏病的发展。这项研究的初步结果表明，这种相互作用 在两种不同的心脏疾病的情况下形成/影响病理表型：CPVT和前DC。基于 根据这些结果以及文献中的数据，假设SR和 线粒体通过调节/塑造细胞内Ca ~（2+）参与Ca ~（2+）依赖性心脏病表型 信号.为了验证这一假设，多尺度研究（从分子到整个动物），采用新的遗传学方法， 小鼠模型，并利用细胞生理学和蛋白质生物化学的方法，沿着体内心脏 功能分析，提出。本研究的总体目标是让本科生：1）定义 决定线粒体对ACR反应的具体方式的分子参与者和因素， 塑造细胞内Ca动力学，并在CPVT与DC前设置中促成心脏病理学，以及2）利用 遗传学方法来探讨直接调节线粒体Ca对心脏病理学的影响， 疾病设置。这项研究具有重要意义，因为它将大大促进对SR的理解。 线粒体Ca信号在CPVT和前DC的设置，从而促进机制的发展- 治疗这些毁灭性的心脏病。它还将作为未来翻译的基础 研究为钙依赖性心脏病的亚型提供量身定制的疗法。此外，该项目将 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。 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.