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
- 来源:
- 关键词:AblationActivities of Daily LivingAddressAffectAmericanArrhythmiaBiological MarkersBlood CirculationBlood PressureCardiacCardiac MyocytesCaringCellsCenters for Disease Control and Prevention (U.S.)Cessation of lifeCitric Acid CycleDataDoseEnzymesFatty AcidsFutureGenerationsGeneticGlucoseGrantHealthHeartHeart failureHumanHydroxybutyratesHypertrophyImpairmentIntervention StudiesIntestinesIntravenousKetonesKnockout MiceLabelLiverMass Spectrum AnalysisMeasuresMediatingMetabolicMetabolismMitochondriaMitochondrial MyopathiesModelingMorbidity - disease rateMusMyocardial InfarctionNiacinamideNicotinamide MononucleotideNicotinamide adenine dinucleotideNicotinic AcidsOralOrganOxidation-ReductionPatientsPhenotypePhysiologyPre-Clinical ModelPredispositionPreventionProteinsPublishingRegimenResearchRodentRodent ModelRoleRouteStable Isotope LabelingSupplementationSurgical ModelsTechniquesTestingTherapeuticTherapeutic EffectTimeTissuesTitrationsTracerTranslationsTransplantationTryptophanbasecofactorconstrictiondietaryexperimental studyfallsheart functionheart rhythmimprovedin vivoinnovationintraperitonealliver metabolismmitochondrial dysfunctionmortalitynicotinamide phosphoribosyltransferasenicotinamide-beta-ribosidenovel therapeutic interventionoxidationpreclinical studyrestorationstable isotopesubcutaneoussudden cardiac deaththerapeutic evaluationtooluptake
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(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:
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