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

基本信息

  • 批准号:
    10539858
  • 负责人:
  • 金额:
    $ 73.34万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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+池的作用和前体补充剂的治疗作用, 心力衰竭 我们正在探索的假设,烟酰胺腺嘌呤二核苷酸(NAD+)代谢可以针对 来改善衰竭心脏的功能NAD+是一种普遍存在的分子, 氧化还原辅因子或细胞内数百种酶的底物。它来源于膳食色氨酸, 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。 NAD+浓度福尔斯在衰竭的人类心脏和一些心力衰竭的啮齿动物模型中下降。高剂量的 包括烟酰胺核苷(NR)和烟酰胺单核苷酸肽(NMN)的前体具有治疗作用, 在啮齿动物模型中的作用。然而,使用的剂量超过了人类可耐受的剂量, 在人类相关剂量下的影响仍然不确定。我们的初步和发表的结果表明,高 在啮齿动物模型中可能需要NR和NMN剂量,因为这两种分子都被广泛代谢 当口服时,在肠道和肝脏中,只有一小部分完整地到达循环。在 相比之下,静脉内递送允许更高比例的剂量到达器官,例如心脏。 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。我们给一只敲除小鼠 心肌细胞特异性NAD+损失损害心脏功能,并提出了一种新的模型的产生 以专门测试线粒体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 1)测试心脏特异性NAD+消耗是否足以概括代谢性NAD+消耗。 目的2)测试替代递送途径是否可以允许心脏起搏, 在小鼠中通过低的人类相关剂量拯救NAD+,目的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导心力衰竭的易感性。我们 使用AAV靶向心脏中的SLC 25A51表达的方法将是第一次调节 已经尝试在体内使用这种蛋白质来改变线粒体NAD+库。这些研究将 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, 开发用于治疗或预防人类患者心力衰竭的新治疗方法。

项目成果

期刊论文数量(0)
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Joseph A. Baur其他文献

Human genetics identify convergent signals in mitochondrial LACTB-mediated lipid metabolism in cardiovascular-kidney-metabolic syndrome
人类遗传学确定了心血管-肾脏-代谢综合征中线粒体 LACTB 介导的脂质代谢中的趋同信号。
  • DOI:
    10.1016/j.cmet.2024.10.007
  • 发表时间:
    2025-01-07
  • 期刊:
  • 影响因子:
    30.900
  • 作者:
    Shen Li;Hongbo Liu;Hailong Hu;Eunji Ha;Praveena Prasad;Brenita C. Jenkins;Ujjalkumar Subhash Das;Sarmistha Mukherjee;Kyosuke Shishikura;Renming Hu;Daniel J. Rader;Liming Pei;Joseph A. Baur;Megan L. Matthews;Garret A. FitzGerald;Melanie R. McReynolds;Katalin Susztak
  • 通讯作者:
    Katalin Susztak
Mitochondrial NAD+ transporter SLC25A51 linked to human aortic disease
线粒体 NAD+转运蛋白 SLC25A51 与人类主动脉疾病相关
  • DOI:
    10.1038/s44161-024-00599-6
  • 发表时间:
    2025-01-22
  • 期刊:
  • 影响因子:
    10.800
  • 作者:
    Gabriel K. Adzika;Ricardo A. Velázquez Aponte;Joseph A. Baur
  • 通讯作者:
    Joseph A. Baur
Swine Models for NAD + Supplementation in Heart Failure
补充 NAD 治疗心力衰竭的猪模型
  • DOI:
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Joseph A. Baur
  • 通讯作者:
    Joseph A. Baur
Resveratrol for primary prevention of atherosclerosis: Clinical trial evidence for improved gene expression in vascular endothelium
  • DOI:
    10.1016/j.ijcard.2012.09.027
  • 发表时间:
    2013-06-05
  • 期刊:
  • 影响因子:
  • 作者:
    Beamon Agarwal;Matthew J. Campen;Meghan M. Channell;Sarah J. Wherry;Behzad Varamini;James G. Davis;Joseph A. Baur;James M. Smoliga
  • 通讯作者:
    James M. Smoliga
Regulation of and challenges in targeting NAD+ metabolism
靶向 NAD+代谢的调控与挑战
  • DOI:
    10.1038/s41580-024-00752-w
  • 发表时间:
    2024-07-18
  • 期刊:
  • 影响因子:
    90.200
  • 作者:
    Marie E. Migaud;Mathias Ziegler;Joseph A. Baur
  • 通讯作者:
    Joseph A. Baur

Joseph A. Baur的其他文献

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{{ truncateString('Joseph A. Baur', 18)}}的其他基金

Mechanisms and therapeutic potential of blocking the mitochondrial Mg2+ channel Mrs2 in obesity and NAFLD
阻断线粒体 Mg2 通道 Mrs2 在肥胖和 NAFLD 中的机制和治疗潜力
  • 批准号:
    10679847
  • 财政年份:
    2023
  • 资助金额:
    $ 73.34万
  • 项目类别:
HTS to identify compounds that increase NAD+ levels in neurons and muscle cells
HTS 鉴定可增加神经元和肌肉细胞中 NAD 水平的化合物
  • 批准号:
    10665088
  • 财政年份:
    2022
  • 资助金额:
    $ 73.34万
  • 项目类别:
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
  • 财政年份:
    2022
  • 资助金额:
    $ 73.34万
  • 项目类别:
HTS to identify compounds that increase NAD+ levels in neurons and muscle cells
HTS 鉴定可增加神经元和肌肉细胞中 NAD 水平的化合物
  • 批准号:
    10618481
  • 财政年份:
    2022
  • 资助金额:
    $ 73.34万
  • 项目类别:
Mechanisms underlying the genetic association between PPP1R3B and Alzheimer's Disease
PPP1R3B 与阿尔茨海默病之间遗传关联的潜在机制
  • 批准号:
    10288770
  • 财政年份:
    2018
  • 资助金额:
    $ 73.34万
  • 项目类别:
Molecular mechanisms underlying the genetic association between PPP1R3B and hepatic steatosis
PPP1R3B与肝脂肪变性遗传关联的分子机制
  • 批准号:
    10224175
  • 财政年份:
    2018
  • 资助金额:
    $ 73.34万
  • 项目类别:
Targeting NAD Metabolism to Improve Glucose Homeostasis in Obesity and Aging
靶向 NAD 代谢以改善肥胖和衰老过程中的血糖稳态
  • 批准号:
    10288703
  • 财政年份:
    2013
  • 资助金额:
    $ 73.34万
  • 项目类别:
Targeting NAD Metabolism to Improve Glucose Homeostasis in Obesity and Aging
靶向 NAD 代谢以改善肥胖和衰老过程中的血糖稳态
  • 批准号:
    8596305
  • 财政年份:
    2013
  • 资助金额:
    $ 73.34万
  • 项目类别:
Targeting NAD Metabolism to Improve Glucose Homeostasis in Obesity and Aging
靶向 NAD 代谢以改善肥胖和衰老过程中的血糖稳态
  • 批准号:
    8731882
  • 财政年份:
    2013
  • 资助金额:
    $ 73.34万
  • 项目类别:
Molecular Mechanisms of Rapamycin's effects on Health and longevity.
雷帕霉素对健康和长寿影响的分子机制。
  • 批准号:
    8852520
  • 财政年份:
    2013
  • 资助金额:
    $ 73.34万
  • 项目类别:

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