Creatine Kinase Metabolism in Failing Murine Hearts

描述（由申请人提供）：本提案旨在测量和操纵小鼠体内通过心肌肌酸激酶（CK）的心流量，以测试心力衰竭（CHF）的能量饥饿假说。正常心脏收缩功能对ATP的需求是绝对的，CK反应是心脏的主要能量库。CK代谢产物在CHF中减少并预测结果。最近，人类心脏中通过CK的ATP通量的第一次直接测量显示，即使在整体[ATP]损失发生之前，CHF中CK通量也会急剧减少50-70%。尽管有这一支持性证据，但常规代谢干预未能增加衰竭心脏中的CK池或流量，以直接测试能量饥饿假说。本申请提出了使用新的转染方法，刚刚开发的研究人员，基因过表达的因素，最有可能限制CK流量在CHF和确定，在体内，能量和功能的后果。具体目标是：（1）。在小鼠研究中实施新的临床MR技术，以评估体内心脏CK代谢物、通量和功能，2.）为了验证CHF中CK表达增加会增加体内心脏CK通量并改善心室功能的假设，3.）为了检验增加肌酸转运蛋白表达将增加CHF中心肌肌酸、CK通量和机械功能的假设，4.）验证条件性CK基因缺失会加重CHF的发展，而CK补救会提供保护的假设。这项提案独特地汇集了新的非侵入性工具来测量体内心脏CK流量，新技术来执行基因CK操作，相关的动物模型，投降的特点，人类CHF，最后，复杂的手段来评估功能的后果。这些小鼠研究提供了在人类CHF中不可能的干预措施，并为这种流行的，不断增长的疾病提供了新的见解。概述：心力衰竭是美国发病率和死亡率的一个重要且不断增长的原因。我们最近对人类心力衰竭的观察指导了这些目前只能在小鼠中进行的研究。我们将使用最先进的技术来增加衰竭小鼠心脏的能量代谢，看看这是否会改善心脏的收缩并减少心力衰竭。

DESCRIPTION (provided by applicant): This proposal aims to measure and manipulate in vivo cardiac flux through myocardial creatine kinase (CK) in mice to test the energy starvation hypothesis of heart failure (CHF). The requirement of ATP for normal cardiac contractile function is absolute and the CK reaction is the major energy reservoir of the heart. CK metabolites are reduced in CHF and predict outcomes. The first direct measures of ATP flux through CK in the human heart recently revealed dramatic 50-70% reductions in CK flux in CHF even before global [ATP] loss occurs. Despite this supporting evidence, conventional metabolic interventions have failed to augment CK pools or flux in failing hearts to directly test the energy starvation hypothesis. This application proposes the use of new transfection approaches, just developed by the investigators, to genetically over-express the factors most likely limiting CK flux in CHF and determine, in vivo, the energetic and functional consequences. The specific aims are: 1.) to implement new clinical MR techniques in mouse studies for assessing in vivo cardiac CK metabolites, flux and function, 2.) to test the hypothesis that increasing CK expression in CHF increases in vivo cardiac CK flux and improves ventricular function, 3.) to test the hypothesis that increasing creatine transport protein expression will increase myocardial creatine, CK flux, and mechanical function in CHF, 4.) to test the hypothesis that conditional CK gene deletion will exacerbate the development of CHF and that CK rescue will provide protection. This proposal uniquely brings together novel non-invasive tools to measure in vivo cardiac CK flux, new technology to perform genetic CK manipulations, relevant animal models that capitulate characteristics of human CHF, and finally, sophisticated means to assess the functional consequences. These mouse studies offer interventions not possible in human CHF and promise new insights for this prevalent, growing disease. Lay summary: Heart failure is an important and growing cause of morbidity and mortality in the United States. Our recent observations in human heart failure guide these studies that currently can only be performed in mice. We will use state-of-the-art techniques to increase energy metabolism in failing mouse hearts and see if that improves the contraction of the heart and reduces heart failure.