NAD metabolism in inherited cardiomyopathies

遗传性心肌病中的 NAD 代谢

• 批准号: 505805397
• 负责人: Professor Dr. Christoph Maack
• 金额: --
• 依托单位: Paris - Centre de Recherche Cardiovasculaire à lHEGP
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/505805397?language=en
• 关键词: NAD; metabolism; inherited; cardiomyopathies

The heart is the most energy consuming organ of the body. Under physiological conditions, proper heart function results from the fine orchestration of ion fluxes, the contractile apparatus, and mitochondrial metabolism in cardiomyocytes. In heart failure (HF), these equilibria are critically disturbed, and energetic mismatch can lead to oxidative stress, maladaptive signalling, structural remodelling and contractile dysfunction. In inherited cardiomyopathies, defects in the sarcomeric apparatus, mitochondrial metabolism or signalling molecules can induce HF with variable phenotypes, spanning from reduced to preserved or even hyperdynamic contractile function. A central molecule to cardiac energy metabolism, redox regulation and signalling is nicotinamide adenine dinucleotide (NAD). Previous studies from members of this consortium revealed that in HF, NAD metabolism is disturbed, and that NAD supplementation improves the cardiac phenotype. However, it is unclear whether these effects are caused by influencing NAD-dependent signaling events or redox regulation interfacing with excitation-contraction coupling, or both. In NADINCARD, three teams combine their complementary expertise to explore the role of NAD metabolism and signalling at the cellular and subcellular level in cardiomyocytes, using animal and human cell-based models of hereditary cardiomyopathies. NADINCARD will identify critical regulatory mechanisms, relevant targets and metabolic pathways governing heart function. We expect that this fundamental research will be translated into long-term opportunities for prevention, screening, monitoring, diagnosis and therapy of inherited cardiomyopathies.

心脏是人体消耗能量最多的器官。在生理条件下，正常的心功能是离子通量、收缩装置和心肌细胞线粒体代谢的精细协调的结果。在心力衰竭（HF）中，这些平衡被严重扰乱，能量错配会导致氧化应激、信号适应不良、结构重塑和收缩功能障碍。在遗传性心肌病中，肌体、线粒体代谢或信号分子的缺陷可诱导具有不同表型的HF，从减少到保留甚至是高动力收缩功能。烟酰胺腺嘌呤二核苷酸（NAD）是心脏能量代谢、氧化还原调节和信号传导的中心分子。该联盟成员先前的研究表明，在HF中，NAD代谢受到干扰，补充NAD可改善心脏表型。然而，目前尚不清楚这些影响是由影响nad依赖的信号事件还是氧化还原调节与兴奋-收缩耦合，或两者兼而有之引起的。在NADINCARD中，三个团队结合他们互补的专业知识，利用动物和人类遗传性心肌病的细胞模型，探索心肌细胞中NAD代谢和信号在细胞和亚细胞水平上的作用。NADINCARD将确定心脏功能的关键调控机制、相关靶点和代谢途径。我们期望这项基础研究将转化为遗传性心肌病的预防、筛查、监测、诊断和治疗的长期机会。