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: 10539858
• 负责人: Joseph A. Baur
• 金额: $ 73.34万
• 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/10539858
• 关键词: Ablation; Activities of Daily Living; Address; Affect; American; Arrhythmia; Biological Markers; Blood Circulation; Blood Pressure; Cardiac; Cardiac Myocytes; Caring; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; 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; 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; base; cofactor; constriction; 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+ 库的作用以及前体补充剂的治疗效果 心脏衰竭 我们正在探索可以靶向烟酰胺腺嘌呤二核苷酸 (NAD+) 代谢的假设 提高衰竭人类心脏的功能能力。 NAD+ 是一种普遍存在的分子，需要作为 细胞内数百种酶的氧化还原辅因子或底物。它源自膳食色氨酸， 烟酸、烟酰胺或合成中间体，但心脏中的大部分合成是通过烟酰胺进行的。 在人类心脏衰竭和某些心力衰竭啮齿动物模型中，NAD+ 浓度会下降。高剂量 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作用 对啮齿动物模型的影响。然而，所使用的剂量超出了人类的耐受范围，并且有潜在的潜在风险。 人体相关剂量的影响仍不确定。我们的初步和公布的结果表明，高 啮齿动物模型中可能需要一定剂量的 NR 和 NMN，因为这两种分子都被广泛代谢 口服时会进入肠道和肝脏，只有一小部分完好无损地到达循环系统。在 相比之下，静脉注射允许更高比例的剂量到达心脏等器官。 除了剂量问题外，保护机制仍不清楚。据推测 涉及心脏 NAD+ 水平，但全身补充研究留下了其他可能性 组织介导保护，例如通过降低血压。我们推出了一种基因敲除小鼠 心肌细胞特异性 NAD+ 损失会损害心脏功能并提出新模型的产生 专门测试线粒体 NAD+ 在心肌细胞内的作用。这将通过以下方式完成 靶向 SLC25A51，我们最近将其确定为线粒体 NAD+ 转运蛋白。我们提出三个 具体目标： 目标 1) 测试心脏特异性 NAD+ 消耗是否足以概括代谢 和心力衰竭的电后果，目标 2) 测试替代输送途径是否可以允许心脏 NAD+ 在小鼠中通过与人类相关的低剂量来挽救，目标 3) 测试是否改变线粒体 NAD+ 本身足以调节心脏功能或改变对诱发心力衰竭的易感性。我们的 使用 AAV 靶向心脏中 SLC25A51 表达的方法将是第一次调节 已在体内尝试过这种蛋白质可以改变线粒体 NAD+ 库。这些研究共同将 揭示 NAD+ 代谢如何影响心脏生理学的基本细节，并将有助于指导工作 开发治疗或预防人类患者心力衰竭的新治疗方法。