Understanding the roles of cardiac NAD pools and therapeutic effects of precursor supplements in heart failure

了解心脏 NAD 池的作用以及前体补充剂对心力衰竭的治疗作用

• 批准号: 10680576
• 负责人: Joseph A. Baur
• 金额: $ 66.1万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-09 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680576
• 关键词: Ablation; Activities of Daily Living; Address; Affect; American; Arrhythmia; Biological Markers; Blood Pressure; Cardiac; Cardiac Myocytes; Caring; Cells; Cessation of life; Circulation; Citric Acid Cycle; Data; Dose; Enzymes; Fatty Acids; Future; Generations; Genetic; Glucose; Grant; Health; Heart; Heart failure; Human; Hydroxybutyrates; Hypertrophy; Impairment; Intervention Studies; Intestines; Intravenous; Ketones; Knockout Mice; Label; Learning; Liver; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Metabolism; Mitochondria; Mitochondrial Myopathies; Modeling; Morbidity - disease rate; Mus; Myocardial Infarction; Niacinamide; Nicotinamide Mononucleotide; Nicotinamide adenine dinucleotide; Nicotinic Acids; Oral; Organ; Oxidation-Reduction; Patients; Phenotype; Physiology; Pre-Clinical Model; Predisposition; Prevention; Proteins; Publishing; Regimen; Research; Rodent; Rodent Model; Role; Route; Stable Isotope Labeling; Supplementation; Surgical Models; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Titrations; Tracer; Translations; Transplantation; Tryptophan; aorta constriction; cofactor; dietary; experimental study; falls; heart function; heart rhythm; improved; in vivo; innovation; intraperitoneal; liver metabolism; mitochondrial dysfunction; mortality; nicotinamide phosphoribosyltransferase; nicotinamide-beta-riboside; novel therapeutic intervention; oxidation; preclinical study; restoration; stable isotope; subcutaneous; sudden cardiac death; therapeutic evaluation; tool; uptake

Understanding the roles of cardiac NAD+ pools and therapeutic effects of precursor supplements in heart failure We are exploring the hypothesis that nicotinamide adenine dinucleotide (NAD+) metabolism can be targeted to improve functional capacity in failing human hearts. NAD+ is a ubiquitous molecule that is required as a redox cofactor or substrate for hundreds of enzymes within the cell. It is derived from dietary tryptophan, niacin, nicotinamide, or synthetic intermediates, but the majority of synthesis in the heart is via nicotinamide. NAD+ concentration falls in failing human hearts and in some rodent models of heart failure. High doses of precursors including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) have therapeutic effects in rodent models. However, the doses used exceed what is tolerable in humans and the potential for effects at human-relevant doses remains uncertain. Our preliminary and published results suggest that high doses of NR and NMN may be required in rodent models because both molecules are extensively metabolized in the intestines and liver when delivered orally, with only a tiny fraction reaching the circulation intact. In contrast, intravenous delivery allows a much higher proportion of the dose to reach organs such as the heart. In addition to questions about dosing, the mechanism of protection has remained unclear. It is presumed to involve cardiac NAD+ levels, but whole-body supplementation studies leave open the possibility that other tissues mediate protection, for example through lowering blood pressure. We present a knockout mouse with cardiomyocyte-specific loss of NAD+ that impairs heart function and propose the generation of a new model to specifically test the role of mitochondrial NAD+ within the cardiomyocytes. This will be accomplished by targeting SLC25A51, which we recently identified as the mitochondrial NAD+ transporter. We propose three specific aims: Aim 1) Test whether heart-specific NAD+ depletion is sufficient to recapitulate the metabolic and electrical consequences of heart failure, Aim 2) Test whether alternate delivery routes can allow cardiac NAD+ to be rescued by low, human-relevant doses in mice, and Aim 3) Test whether altering mitochondrial NAD+ is sufficient to modulate heart function on its own or modifies susceptibility to induced heart failure. Our approach of using AAV to target SLC25A51 expression in the heart will be the first time that modulation of this protein to alter the mitochondrial NAD+ pool has been attempted in vivo. Together, these studies will reveal fundamental details of how NAD+ metabolism influences cardiac physiology, and will help guide efforts to develop novel therapeutic approaches for the treatment or prevention of heart failure in human patients.

了解心脏NAD+池的作用以及前体补充剂在 心脏衰竭 我们正在探讨烟酰胺腺嘌呤二核苷酸（NAD+）代谢的假设 提高失败人心的功能能力。 NAD+是一种无处不在的分子 细胞内数百种酶的氧化还原辅因子或底物。它来自饮食色氨酸， 烟酸，烟酰胺或合成中间体，但心脏中的大多数是通过烟酰胺。 NAD+浓度落在失败的人心脏和一些心力衰竭的啮齿动物模型中。高剂量的 包括烟酰胺核苷（NR）和烟酰胺单核苷酸（NMN）在内的前体具有治疗性 在啮齿动物模型中的影响。但是，所使用的剂量超过了人类可忍受的 与人相关剂量的影响仍然不确定。我们的初步和发表的结果表明 在啮齿动物模型中可能需要NR和NMN的剂量，因为两个分子都是广泛代谢的 口服传递时的肠和肝脏中，只有很小的部分完整地达到循环。在 对比，静脉输送允许剂量的更高比例到达心脏等器官。 除了有关给药的问题外，保护机理还不清楚。假定 涉及心脏NAD+水平，但是全身补充研究使其他可能性 组织介导保护，例如通过降低血压。我们提出了一只淘汰鼠标 损害心脏功能并提出新模型的NAD+的心肌细胞特异性损失 要专门测试线粒体NAD+在心肌细胞中的作用。这将通过 靶向SLC25A51，我们最近确定为线粒体NAD+转运蛋白。我们提出了三个 具体目的：目标1）测试心脏特异性的NAD+耗竭是否足以概括代谢 和心力衰竭的电气后果，目标2）测试替代递送路线是否可以允许心脏 NAD+将通过小鼠中低的人含量剂量营救，目标3）测试是否改变线粒体 NAD+足以自行调节心脏功能或改变对诱发心力衰竭的敏感性。我们的 在心脏中使用AAV靶向SLC25A51表达的方法是首次调制 这种蛋白质改变了线粒体NAD+池的蛋白质已在体内尝试。这些研究将在一起 揭示NAD+代谢如何影响心脏生理的基本细节，并将帮助指导努力 开发新的治疗方法，以治疗或预防人类患者的心力衰竭。