Glycemic Origins of Endothelial Dysfunction

内皮功能障碍的血糖起源

• 批准号: 10338109
• 负责人: Caleb A Padgett
• 金额: $ 2.71万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-07-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10338109
• 关键词: Arteries; Automobile Driving; Binding; Biological Availability; Biology; Blood Vessels; Blood capillaries; Carbohydrates; Cardiovascular Diseases; Cells; Chemistry; Clinical Research; Complex; Data; Disease; Disease Resistance; Endothelial Cells; Endothelium; Equilibrium; Exhibits; Funding; GDF8 gene; Galectin 3; Glucose; Health; Hindlimb; Impairment; Ischemia; Kidney Diseases; Knock-out; Knockout Mice; Laboratories; Lectin; Ligation; Link; Lipids; Measurement; Measures; Mediating; Mentorship; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Metformin; Modeling; Mus; Myography; NADPH Oxidase; NADPH Oxidase 1; NOS3 gene; Nitric Oxide; Obese Mice; Obesity; Outcome; Oxidants; Oxidative Stress; Paint; Pathology; Pathway interactions; Perfusion; Plasma; Process; Production; Protein Isoforms; Radio; Reactive Oxygen Species; Recording of previous events; Recovery; Research; Resistance; Retinal Diseases; Role; Signal Transduction; Superoxides; Technical Expertise; Telemetry; Testing; Therapeutic; Thinness; United States; Universities; Vascular Diseases; Weight Gain; Work; cardiovascular health; cardiovascular risk factor; catalyst; cost; db/db mouse; endothelial dysfunction; experimental study; glucose metabolism; glucose tolerance; glycemic control; improved; in vivo; insight; insulin sensitivity; insulin tolerance; limb ischemia; medical schools; mouse model; muscle form; novel; overexpression; oxidant stress; post-doctoral training; pre-doctoral; pressure; receptor for advanced glycation endproducts; therapeutic target

PROJECT SUMMARY Obesity has been well-documented as a major risk factor for cardiovascular disease. Our lab has demonstrated that increases in reactive oxygen species (ROS) produced by NADPH Oxidase 1 (NOX1) have been shown to contribute to endothelial dysfunction, a hallmark of obesity-driven cardiovascular disease. Our studies suggest that galectin-3 (GAL-3), an advanced glycation end-product receptor associated with cardiovascular disease, may be a mechanistic link between aberrant glycemic control found in obesity and disruption of metabolism driving vascular disease. Additionally, hypermuscular obese mice have been shown to exhibit greater glycemic control and ameliorated endothelial dysfunction. However, the mechanisms by which GAL-3 drives vascular disease are poorly understood. Therefore, the central hypothesis of this proposal is that GAL-3 is the link between metabolic dysfunction and NOX-1 mediated impairment of endothelial health. This hypothesis will be tested in two specific aims. Aim 1 will test the hypothesis that metabolic dysfunction drives expression of GAL-3 and NOX1. We will assess endothelial expression of GAL-3, NOX1, and attendant co-factors in lean and obese mice, as well as in obese mice with improved metabolism by either myostatin knockout or treatment with metformin or dapagliflozin. Additionally, we will utilize a novel db/db/GAL-3 knockout mouse to asses the role of GAL-3 in mediating expression of NOX 1 and vascular oxidative stress. Aim 2 will test the hypothesis that GAL- 3 is the link between metabolic dysfunction and impaired endothelial function. Utilizing the novel mouse model generated above, we will assess overall metabolic status, as well as endothelial function using pressure myography on resistance microvessels. Finally, in vivo vascular function will be assessed using radiotelemetry to measure arterial pressure and a hind limb ischemia model to investigate recovery of perfusion.This project will allow me to develop new technical skills such as pressure myography and radio telemetry, and will allow me to gain expertise in conducting rigorous, hypothesis-driven research. The project will be conducted under the mentorship of Dr. David Stepp in the Vascular Biology Center at the Medical College of Georgia at Augusta University, which has a rich history of successful pre- and post-doctoral training. The proposed project is for 3 years of funding with the proposed aims divided amongst the 3 years of funding, culminating with a dissertation defense at the end of the third year. We anticipate that findings from this novel proposal will identify injurious overexpression of GAL-3 as a key determinant of NOX1-mediated endothelial dysfunction in obesity-induced metabolic disease and will provide insight into avenues for potential therapeutics to restore oxidative balance and improve cardiovascular health.

项目总结 肥胖已被证明是心血管疾病的一个主要风险因素。我们的实验室已经证明 NADPH氧化酶1(NOX1)产生的活性氧物种(ROS)的增加已被证明 导致内皮功能障碍，这是肥胖引发的心血管疾病的一个标志。我们的研究表明 Galectin-3(GAL-3)是一种与心血管疾病相关的晚期糖基化终产物受体， 可能是肥胖患者血糖控制异常和新陈代谢紊乱之间的机械联系 导致血管疾病。此外，肌肉发达的肥胖小鼠表现出更高的血糖水平。 控制和改善内皮功能障碍。然而，GAL-3驱动血管的机制 人们对疾病知之甚少。因此，这一提议的中心假设是GAL-3是联系 代谢功能障碍与NOX-1介导的内皮健康损害之间的关系。这一假设将是 在两个特定的目标上进行了测试。目标1将验证代谢功能障碍驱动GAL-3表达的假设 和NOX1。我们将评估瘦身和肥胖者GAL-3、NOX1和伴随的辅助因子的内皮表达 小鼠，以及通过Myostatin基因敲除或用 二甲双胍或达帕利嗪。此外，我们将利用一种新的db/db/ga-3基因敲除小鼠来评估 Gal-3在介导NOX-1表达和血管氧化应激中的作用目标2将检验假设，GAL- 3是代谢紊乱和内皮功能受损之间的联系。利用新的鼠标模型 在上面生成的，我们将评估整体代谢状态，以及使用压力来评估内皮功能 阻力微血管的肌造影术。最后，体内血管功能将使用无线电遥测进行评估。 测量动脉压和后肢缺血模型以研究血流灌注的恢复。 将使我发展新的技术技能，如压力肌图术和无线电遥测，并将使我 在进行严谨的、假设驱动的研究方面获得专业知识。该项目将在 大卫·斯特普博士在奥古斯塔乔治亚医学院血管生物学中心的指导 这所大学有着成功的博士后和博士后培训的丰富历史。建议的项目为3个 三年的资助，最后是一篇论文 在第三年结束时进行辩护。我们预计，这项新提案的结果将确定有害的 肥胖大鼠GAL-3过度表达是NOX1介导的内皮功能障碍的关键决定因素 并将为恢复氧化平衡的潜在治疗方法提供洞察力 并改善心血管健康。