The regulation of BRD7 in glucose homeostasis

项目摘要 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， 这是一个挑战，它仍然是难以捉摸的。目前，2型糖尿病还没有治愈方法， 肥胖症的治疗方法。为了找到治疗靶点，重要的是了解 肥胖的病理生理学和胰岛素抵抗发展的分子机制。 最近，有报道称，一种被称为含溴结构域蛋白7的蛋白质的表达水平与其在细胞中的表达水平相关。 （BRD7）在肥胖小鼠的肝脏中显著减少。此外，已经表明，恢复 肥胖和糖尿病小鼠肝脏中的BRD7降低血糖水平并改善葡萄糖耐量。 因此，很明显BRD7参与葡萄糖稳态的调节。这项建议旨在 研究BRD7改善葡萄糖耐量和胰岛素敏感性新分子机制。 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。 肥胖者的糖尿病。 这个项目涉及胰岛素信号传导中的几种新的机制途径。其中包括理解 BRD7如何导致胰岛素受体信号转导对胰岛素的反应发生改变，以及肝葡萄糖 生产和血糖水平由BRD7调节。在目标1中，基因工程小鼠模型 将用于定义BRD7在胰岛素信号通路中的作用。这些实验的结果将 揭示了一种控制胰岛素受体信号传导的新机制。在Aim 2中，几种小鼠模型 和细胞系将被用来了解糖原和脂质的调控BRD7。的结果 目标3下的实验将提供对BRD7调节的更好理解。成功结果 这一建议将提高2型糖尿病领域的科学知识，并提出一种替代方案。 这不仅是治疗2型糖尿病的一种方法，而且还可以预防胰岛素抵抗和葡萄糖的发展。 肥胖患者的不耐受。

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.