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

探索线粒体在患病心脏钙处理失调中的作用

基本信息

批准号：
10202296
负责人：
Bin Liu
金额：
$ 42.27万
依托单位：
MISSISSIPPI STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-10 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10202296
关键词：
Affect Animals Arrhythmia Biochemical Biological Assay Buffers Calcium Cardiac Catecholaminergic Polymorphic Ventricular Tachycardia Cause of Death Cell Death Cell physiology Cells Chronic Complex Data Defect Development Disease Disease model Fostering Foundations Functional disorder Future Generations Genetic Genetic Models Goals Heart Heart Abnormalities Heart Diseases Heart failure Homeostasis Image Intervention Knowledge Life Link Literature Mediating Membrane Potentials Metabolic Metabolic Diseases Methods Mitochondria Molecular Mus Muscle Cells Mutation Outcome Pathologic Pathology Pharmaceutical Preparations Phenotype Phosphorylation Physiological Play Prediabetes syndrome Production Protein Biochemistry Proteins Research Role Ryanodine Receptor Calcium Release Channel Ryanodine Receptors Sarcoplasmic Reticulum Shapes Signal Transduction Structure Syndrome Techniques Testing Translating United States base calmodulin-dependent protein kinase II career diabetic cardiomyopathy disease phenotype genetic approach heart function heart rhythm in vivo individualized medicine insight mitochondrial permeability transition pore mouse model novel novel therapeutics oxidation translational study undergraduate student

项目摘要

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.

心脏病仍然是美国的主要死亡原因。 CA释放的改变肌质网（SR）由于遗传和获得的缺陷在Ca释放通道中，瑞氨烷受体中的缺陷（RYR2）被认为是一系列毁灭性心脏疾病的基础，从心律不齐到心脏失败。 RYR2功能障碍，主要表现为异常活跃（即泄漏）通道，导致异常CA 释放（ACR）。但是，尽管建立了ACR在促进各种疾病状态的关键作用，但尚不清楚为什么以及如何以及如何使用相同的基础缺陷，即异常CA释放，导致不同不同疾病环境中的病理表型。例如，ACR导致心律不齐没有儿茶酚胺能多态性心动过速（CPVT）中的病理重塑，这是一种威胁生命的遗传心律不齐综合征。相反，ACR与病理重塑和心律不齐有关在糖尿病前心肌病（DC）的代谢疾病模型中。结果的分歧表明除泄漏的RYR2之外，这些因素对于将异常的RYR2 CA释放到特定疾病至关重要状态，但是关于异常肌细胞处理之间的联系的知识差距存在差距和心脏病。线粒体感知细胞内Ca信号以介导能量产生和细胞死亡。最近，SR和线粒体之间的相互作用已成为开发不同的心脏病理。这项研究的初步结果表明此相互作用在两种不同的心脏病的设置中，形状/影响病理表型：CPVT和PERED-DC。基于关于这些结果以及文献中的数据，假设SR和SR之间的相互作用线粒体通过调节/塑造细胞内CA来促进CA依赖性心脏病表型信号。为了检验这一假设，多尺度研究（从分子到整个动物）采用了新的遗传小鼠模型并利用细胞生理学和蛋白质生物化学的方法以及体内心脏提出了功能测定。这项研究的总体目标是让本科生参与：1）定义确定线粒体如何对ACR响应ACR的特定方式的分子参与者和因素塑造细胞内CA动力学，并有助于CPVT与DC PREDC设置中的心脏病理，并且2）使用探索直接调节线粒体CA对心脏病理的影响的遗传方法疾病环境。拟议的研究很重要，因为它将大大提高对SR-的理解线粒体CA信号在CPVT和DC的设置中，从而促进了机理的发展这些毁灭性心脏病的基于疗法。它也将成为未来翻译的基础研究为CA依赖性心脏病的亚型提供量身定制的疗法。而且，这个项目将为本科生提供许多参与研究的机会，从而为他们做好充分的准备用于科学或生物医学有关的职业。