The regulation of BRD7 in glucose homeostasis

BRD7 对葡萄糖稳态的调节

• 批准号: 10408691
• 负责人: Sang Won Park
• 金额: $ 44.25万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-17 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408691
• 关键词: Address; Affect; Binding Proteins; Blood Glucose; Bromodomain; Cell Line; Cells; Data; Development; Diabetic mouse; Down-Regulation; Endoplasmic Reticulum; FOXO1A gene; Functional disorder; Genetically Engineered Mouse; Glucose; Glucose Intolerance; Glycogen; Glycogen (Starch) Synthase; Goals; Hepatic; Hormones; IRS1 gene; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Knock-out; Knockout Mice; Knowledge; Lead; Link; Lipids; Liver; Mediating; Metabolism; Methods; Modeling; Molecular; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Translocation; Nutrient; Obese Mice; Obesity; Outcome; Pathology; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Prevention; Proteins; Proto-Oncogene Proteins c-akt; Receptor Signaling; Regulation; Reporting; Research; Resistance development; Role; Signal Transduction; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Type 2 diabetic; base; blood glucose regulation; experimental study; glucose metabolism; glucose production; glucose tolerance; glycogen synthase kinase 3 beta; improved; insulin mediators; insulin sensitivity; insulin signaling; interest; lipid biosynthesis; mouse model; novel; obese patients; obese person; prevent; receptor; response; restoration; therapeutic target; transcription factor

PROJECT SUMMARY Obesity is the major pathology underlying the development of insulin resistance and type 2 diabetes. Despite extensive research, identifying the molecular link between obesity and type 2 diabetes has been a big challenge and it still remains elusive. Currently, there is no cure for type 2 diabetes and no therapeutic treatment methods for obesity. In order to find a therapeutic target, it is important to understand the pathophysiology of obesity and the molecular mechanism by which insulin resistance develops. Recently, it has been reported that the expression levels of a protein called bromodomain-containing protein 7 (BRD7) are significantly reduced in the liver of obese mice. Furthermore, it has been shown that restoration of BRD7 in the liver of obese and diabetic mice reduces blood glucose levels and improves glucose tolerance. Therefore, it is evident that BRD7 is involved in the regulation of glucose homeostasis. This proposal aims to investigate a novel molecular mechanism by which BRD7 improves glucose tolerance and insulin sensitivity. The ultimate goal of this project is to understand whether BRD7 can serve as a novel target to treat type 2 diabetes in obese individuals. This project addresses several novel mechanistic pathways in insulin signaling. These include understanding how BRD7 leads to the alteration of insulin receptor signaling in response to insulin, and how hepatic glucose production and blood glucose levels are regulated by BRD7. In Aim 1, genetically engineered mouse models will be used to define the role of BRD7 in the insulin signaling pathway. The outcome of these experiments will reveal a novel mechanism by which insulin receptor signaling is controlled. In Aim 2, several mouse models and cell lines will be utilized to understand the regulation of glycogen and lipids by BRD7. The results of experiments under Aim 3 will provide a better understanding of the regulation of BRD7. Successful outcomes of this proposal will improve scientific knowledge in the field of type 2 diabetes, and also suggest an alternative way to not only treat type 2 diabetes, but also prevent the development of insulin resistance and glucose intolerance in obese patients.

项目总结 肥胖是胰岛素抵抗和2型糖尿病发展的主要病理基础。尽管 广泛的研究，确定肥胖和2型糖尿病之间的分子联系一直是一个很大的 挑战，它仍然是难以捉摸的。目前，没有治愈2型糖尿病的方法，也没有治疗方法 肥胖症的治疗方法。为了找到治疗靶点，重要的是要了解 肥胖的病理生理学和胰岛素抵抗发生的分子机制。 最近，有报道称，一种名为溴域包含蛋白7的蛋白质的表达水平 (BRD7)在肥胖小鼠的肝脏中显著减少。此外，已经表明，修复 肥胖和糖尿病小鼠肝脏中的BRD7可降低血糖水平，改善葡萄糖耐量。 由此可见，BRD7参与了葡萄糖稳态的调节。这项建议旨在 研究BRD7改善糖耐量和胰岛素敏感性的新分子机制。 该项目的最终目标是了解BRD7是否可以作为治疗2型糖尿病的新靶点 肥胖人群中的糖尿病。 这个项目解决了胰岛素信号传递中的几个新的机制途径。其中包括了解 BRD7如何导致胰岛素受体信号的改变以响应胰岛素，以及肝脏葡萄糖如何 生产和血糖水平由BRD7调节。在AIM 1中，转基因小鼠模型 将被用来定义BRD7在胰岛素信号通路中的作用。这些实验的结果将是 揭示了一种控制胰岛素受体信号的新机制。在《目标2》中，几个小鼠模型 并将利用细胞系来了解BRD7对糖原和血脂的调节。结果是 目标3下的实验将提供对BRD7调控的更好理解。成功的结果 这项建议将提高2型糖尿病领域的科学知识，并提出了一种替代方案 不仅治疗2型糖尿病，而且还能预防胰岛素抵抗和血糖的发展 肥胖患者的不耐受。