Significance and molecular mechanisms of uncoupling protein 2 during insulin secretion in pancreatic ß-cells

2型糖尿病不仅是死亡的主要原因之一，而且还增加了其他慢性疾病的风险。为了治疗这种功能障碍，我们必须增加对控制血糖水平的胰腺β细胞分泌胰岛素的基本分子方面的理解。最近，已经证明线粒体解偶联蛋白2（UCP 2）控制β细胞胰岛素分泌。尽管大量研究表明UCP 2在调节胰岛β细胞胰岛素分泌中起关键作用，但UCP 2的功能及其调节的分子机制尚不清楚，本研究旨在了解UCP 2蛋白在INS 1 β细胞中的作用机制及其调节机制。与以前的体外研究相比，UCP 2激活剂/抑制剂的作用将通过使用细胞生物能量学中的生命成像和新型复杂的高通量技术进行原位测试和监测。基于所有已知UCP 2序列与功能调节剂相互作用的全面生物信息学比对的突变研究将鉴定关键蛋白质基序，从而鉴定潜在的治疗靶点。最后，将在分离的β-胰岛动物模型中测试UCP 2功能的效应子，包括UCP 2敲除小鼠和肥胖诱导的糖尿病表型。

Type 2 diabetes is not only one of the leading causes of death, but it also increases the risk for other chronic diseases. In order to treat this malfunction, we have to increase our understanding of the fundamental molecular aspects of insulin secretion from the pancreatic β-cell controlling blood glucose levels. Recently, it has been demonstrated that mitochondrial uncoupling protein 2 (UCP2) controls β-cell insulin secretion. Although significant studies demonstrated a key role of UCP2 in the regulation of insulin secretion in pancreatic β-cells, the molecular mechanisms of UCP2 function and its regulation are not understood.This research proposal aims to understand UCP2 protein mechanisms and how they can be regulated in the INS1 β-cell. In contrast to previous in vitro studies, the effect of UCP2 activators/inhibitors will be tested and monitored in situ by using life imaging and novel sophisticated high-throughput technologies in cellular bioenergetics. Mutational studies based on a comprehensive bioinformatical alignment of all known UCP2 sequences combined with functional modulator interaction will identify crucial protein motifs and therefore potential therapeutical targets. Finally, effectors of UCP2 function will be tested in isolated β-islets of animal models, including UCP2 knockout mice and obesity-induced diabetic phenotypes.