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

2型糖尿病不仅是主要的死亡原因之一，而且还增加了其他慢性病的风险。为了治疗这一故障，我们必须增加我们对胰腺β细胞控制血糖水平的胰岛素分泌的基本分子方面的理解。最近发现线粒体解偶联蛋白2(UCP2)控制β细胞胰岛素的分泌。虽然大量研究表明UCP2在调节胰腺β细胞胰岛素分泌中起关键作用，但UCP2的功能及其调控的分子机制尚不清楚。本研究旨在了解UCP2蛋白的作用机制及其在β细胞中的调控机制。与之前的体外研究不同，UCP2激活剂/抑制剂的效果将通过生命成像和细胞生物能量学中先进的高通量新技术进行现场测试和监测。突变研究基于对所有已知UCP2序列的全面生物信息比对，结合功能调节剂的相互作用，将确定关键的蛋白质基序，从而确定潜在的治疗靶点。最后，UCP2功能的效应器将在分离的β-胰岛动物模型中进行测试，包括UCP2基因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.