Glycemic Origins of Endothelial Dysfunction

项目摘要 肥胖已被充分证明是心血管疾病的主要危险因素。我们的实验室已经证明 由NADPH氧化酶1（NOX 1）产生的活性氧（ROS）的增加已被证明， 导致内皮功能障碍，这是肥胖导致的心血管疾病的标志。我们的研究表明 半乳糖凝集素-3（GAL-3），一种与心血管疾病相关的晚期糖基化终产物受体， 可能是肥胖症中发现的异常血糖控制和代谢破坏之间的机制联系 导致血管疾病此外，肌肉过多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驱动血管生成的机制是， 疾病知之甚少。因此，该提议的中心假设是GAL-3是连接 代谢功能障碍和NOX-1介导的内皮健康损害之间的关系。这一假设将是 在两个具体目标中进行测试。目的1将检验代谢功能障碍驱动GAL-3表达的假设 NOX1我们将评估在瘦型和肥胖型中GAL-3、NOX 1和伴随的辅助因子的内皮表达， 小鼠，以及通过肌肉生长抑制素敲除或用 二甲双胍或达格列净。此外，我们将利用一种新的db/db/GAL-3敲除小鼠来评估 GAL-3介导NOX 1表达和血管氧化应激。目标2将检验GAL- 3是代谢功能障碍和内皮功能受损之间的联系。利用新型小鼠模型 我们将评估总体代谢状态，以及使用压力的内皮功能 阻力微血管造影。最后，将使用无线电遥测技术评估体内血管功能 测量动脉压和后肢缺血模型，以研究灌注的恢复。本项目 将使我能够发展新的技术技能，如压力肌描记术和无线电遥测，并将使我 以获得进行严格的假设驱动的研究的专业知识。该项目将在 大卫斯特普博士在奥古斯塔的格鲁吉亚医学院血管生物学中心的指导 这所大学拥有成功的博士前和博士后培训的丰富历史。该项目为3 年的资金与拟议的目标分为3年的资金，最终与论文 在第三年年底的防守。我们预计，这项新提案的发现将确定有害的 GAL-3过表达是肥胖诱导的NOX 1介导的内皮功能障碍的关键决定因素 代谢性疾病，并将提供深入了解潜在的治疗方法，以恢复氧化平衡 改善心血管健康。

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.