Mechanisms of mitochondrial calcium exchange in heart failure

描述（由申请人提供）：心力衰竭（HF）的发病率预计在未来20年内将增加25%，预计成本为697亿美元，这对美国造成了巨大的健康和经济负担。一般而言，HF的特征在于收缩性降低和适应不良的心室重构，最终导致体循环的心输出量受损。大量的科学工作集中在解开驱动心脏收缩力降低的分子和细胞机制上，虽然许多变化无疑是原因之一，但人们普遍认为，大部分收缩缺陷是由于细胞溶质钙（Ca 2+）瞬变减少和肌浆网（SR）Ca 2+含量减少。类似地，最近的研究支持这样的理论，即尽管舒张期Ca 2+升高，但HF中线粒体Ca 2+含量实际上减少。为了研究线粒体Ca 2+在HF发展和进展中的作用，我们开发了一种线粒体Na+/Ca 2+交换器（mitoNCX）的突变小鼠模型。线粒体Ca 2+微区由于其对能量产生和细胞死亡的显著影响而受到广泛研究，特别是HF，其特征在于显著的代谢功能障碍和逐渐的细胞脱落。这个项目正在测试一个核心假设， 减少mitoCa 2+流出通过增强心肌细胞代谢和氧化还原能力来防止心力衰竭中的逐渐细胞脱落和不利重塑。这是第一次，利用遗传获得和功能丧失的方法，我们将表征这种新型交换器的生物物理特性，评估其对细胞生理学的贡献，并研究其在临床相关动物模型中的作用。这项奋进的最终目标是确定mitoCa 2+信号在HF发生和发展中的作用，并促进治疗应用。

DESCRIPTION (provided by applicant): The incidence of heart failure (HF) is projected to increase by 25% over the next 20 years with a projected cost of $69.7 billion representing a substantial health and economic burden on the US. In general, HF is characterized by a decrease in contractility and maladaptive ventricular remodeling ultimately leading to impaired cardiac output to the systemic circulation. Immense scientific effort has been focused on unraveling the molecular and cellular mechanisms driving decreased cardiac contractility and while a multitude of changes no doubt contribute, it is generally agreed that much of the contractile deficit is due to a reduction in cytosolic calcium (Ca2+) transients and a decrease in sarcoplasmic reticulum (SR) Ca2+ content. Similarly, recent studies have supported the theory that mitoCa2+ content is actually diminished in HF despite elevations in diastolic Ca2+. To examine the role of mitoCa2+ in the development and progression of HF we have developed mutant mouse models of a proposed mitochondrial Na+/Ca2+ exchanger (mitoNCX). The mitoCa2+ microdomain has been under intense investigation due to its significant influence on energy production and cell death and HF in particular, is characterized by both significant metabolic dysfunction and gradual cell dropout. This project is testing the central hypothesis that reducing mitoCa2+ efflux protects against gradual cell dropout and adverse remodeling in heart failure by enhancing cardiomyocyte metabolic and redox capacity. For the first time, utilizing genetic gain- and loss-of-function approaches we will characterize the biophysical properties of this novel exchanger, assess its contribution to cellular physiology and examine its role in clinically relevant animal models. The ultimate goal of this research endeavor is to define the role of mitoCa2+ signaling in the development and progression of HF and foster therapeutic application.