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年将增加25%，预计成本为697亿美元，对美国来说是一个巨大的健康和经济负担。一般来说，心衰的特点是收缩力下降和不适应的心室重构，最终导致向体循环的心输出量受损。巨大的科学努力已经集中在揭示驱动心脏收缩性下降的分子和细胞机制，虽然许多变化无疑是有贡献的，但人们普遍认为，大部分收缩缺陷是由于胞质钙（Ca2+）瞬态减少和肌浆网（SR） Ca2+含量减少。同样，最近的研究也支持这样的理论，即尽管舒张期Ca2+升高，但心衰患者的mitoCa2+含量实际上是降低的。为了研究mitoCa2+在HF发生和发展中的作用，我们开发了线粒体Na+/Ca2+交换器（mitoNCX）的突变小鼠模型。由于mitoCa2+微结构域对能量产生和细胞死亡的重要影响，特别是HF，其特征是显著的代谢功能障碍和逐渐的细胞脱落，因此受到了广泛的研究。这个项目正在测试一个中心假设

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.