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

在美国，心脏病仍然是导致死亡的主要原因。改变Ca释放

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.