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Role of vascular smooth muscle Bcl11b in arterial stiffness

血管平滑肌 Bcl11b 在动脉僵硬度中的作用

基本信息

批准号：
10393739
负责人：
Francesca Seta
金额：
$ 16.5万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10393739
关键词：
Aging American Angiotensins Animals Anti-Inflammatory Agents Antioxidants Aorta Arteries Attenuated Binding Biological Blood Blood Pressure Blood Vessels Caloric Restriction Cardiovascular Diseases Cardiovascular system Carotid Arteries Cause of Death Cell physiology Cells Chromatin Clinical Clinical Trials Cyclic GMP DNA biosynthesis Deacetylase Diabetes Mellitus Diet Dietary Supplementation Dissection Dose Enzymes Epigenetic Process Equilibrium Event Fatty acid glycerol esters Female Genes Goals Gold Half-Life Harvest Health Care Costs Heart Heart failure Histone Deacetylase Homeostasis Hypertension Individual Knowledge Laboratories Lead Mammals Measures Mediator of activation protein Mesenteric Arteries Metabolic Modeling Molecular Morbidity - disease rate Mus Names Natural regeneration Neurons Niacinamide Nicotinamide Mononucleotide Nicotinamide adenine dinucleotide Nicotinic Acids Obese Mice Obesity Oral Administration Overweight Oxidants Oxidation-Reduction Parents Pathway interactions Physiologic pulse Placebos Population Public Health Rattus Research Research Proposals Risk Risk Factors Role SIRT1 gene Signal Pathway Signaling Molecule Smooth Muscle Myocytes Sucrose Supplementation T-Lymphocyte Therapeutic Tryptophan Type 2 diabetic Vascular Diseases Vascular Smooth Muscle aged arterial stiffness base biological adaptation to stress cardiovascular risk factor combat diabetic dietary supplements enzyme activity high risk human data in vivo indexing longevity gene male mortality nicotinamide riboside supplementation nicotinamide-beta-riboside novel therapeutic intervention obesity prevention oral supplementation overexpression parent grant pre-clinical preservation prevent programs promoter recruit renal artery side effect transcription factor treatment duration trend

项目摘要

Nicotinamide adenine dinucleotide (NAD+) is an essential co-factor for the activity of enzymes involved in cellular metabolic homeostasis, redox balance, DNA synthesis, and stress response. NAD+ is synthetized de novo from tryptophan, but its function is so fundamental to cellular function that mammals evolved a salvage pathway to continuously replenish intracellular NAD+ using a variety of substrates. Among NAD+ precursors, nicotinamide (NAM), nicotinamide mononucleotide (NMN), and nicotinamide riboside (NR) are commercially available as dietary supplements; however, we do not fully understand the full spectrum of their biological effects, specifically on the cardiovascular system, which will be the focus of this research proposal. Of clinical importance, NAD+ levels have been shown to drastically decrease with obesity and aging, which are the highest risk factors for cardiovascular disease (CVD). We postulate that replenishing intracellular NAD+ via dietary supplements is a viable approach to attenuating CVD, which remain the primary cause of morbidity and mortality in an increasingly obese and aging American population. Recent evidence indicate that administering NAM and NMN to experimental animals significantly increases NAD+ levels in heart and fat, preventing diabetes and diabetic heart failure in obese mice/rats. Moreover, NMN has been shown to prevent arterial stiffening and hypertension in aged mice. However, whether dietary supplementation of NMN or NR increases NAD+ levels in the vasculature and whether these increased levels lead to molecular mechanisms with potentially beneficial vascular effects are not fully understood. The goal of this supplemental proposal is to investigate whether dietary supplementation of NMN, NR, or a combination of the two supplements to mice increases NAD+ levels in the vasculature (Aim 1). We will also determine whether this supplementation can preserve vascular function, measured as arterial compliance and blood pressure, in obese and aged mice, by increasing NAD+ levels in vascular cells and activating downstream anti- inflammatory and anti-oxidant pathways (Aim 2). Successful completion of these preclinical, proof-of- concept studies will fill a gap in knowledge on the vascular effects of NAD+ precursors and will guide rational use of NAD+ precursors (NMN, NR) as dietary supplements.

烟酰胺腺嘌呤二核苷酸（NAD+）是参与酶活性的重要辅因子在细胞代谢稳态、氧化还原平衡、DNA合成和应激反应中。NAD+是从色氨酸重新合成，但其功能对细胞功能至关重要，进化出一种补救途径，使用各种底物持续补充细胞内NAD+。在NAD+前体中，烟酰胺（NAM）、烟酰胺单核苷酸（NMN）和烟酰胺核糖核苷（NR）作为膳食补充剂可商购获得;然而，我们并不完全了解其生物学效应的全部范围，特别是对心血管系统的影响，这将是本研究的重点。具有临床重要性的是，NAD+水平已被证明是显著的，随着肥胖和衰老而减少，这是心血管疾病（CVD）的最高风险因素。我们假设通过膳食补充剂补充细胞内NAD+是一种可行的方法，减少CVD，这仍然是发病率和死亡率的主要原因，在日益肥胖的人美国人口老龄化。最近的证据表明，给予NAM和NMN，实验动物显著增加心脏和脂肪中的NAD+水平，预防糖尿病，肥胖小鼠/大鼠的糖尿病心力衰竭。此外，NMN已被证明可以防止动脉硬化和老年小鼠的高血压。然而，无论是NMN或NR的膳食补充增加，血管系统中的NAD+水平以及这些水平的增加是否导致了血管系统中的分子机制。潜在的有益的血管效应还没有完全被理解。本补充提案的目的是是调查是否膳食补充NMN，NR，或两种补充剂的组合，增加血管系统中的NAD+水平（目的1）。我们还将确定这是否补充可以保护血管功能，测量为动脉顺应性和血压，在肥胖和老年小鼠中，通过增加血管细胞中的NAD+水平和激活下游抗- 炎症和抗氧化途径（目的2）。成功完成这些临床前，概念研究将填补NAD+前体对血管影响的知识空白，合理使用NAD+前体（NMN，NR）作为膳食补充剂。