Role and regulation of GLP-1 receptor trafficking in pancreatic beta cells

2型糖尿病和肥胖症是两个相互关联的重大公共卫生问题，由于它们的流行比例，并与心血管疾病和癌症等不良后果有关。2型糖尿病患者经常经历胰岛β细胞衰竭，导致胰岛素的产生和分泌减少。胰升糖素样肽-1受体激动剂(GLP-1R)是一类治疗2型糖尿病的新型药物，它激活GLP-1R，进而刺激胰岛β细胞释放胰岛素，比其他疗法更好地控制血糖水平，同时增加β细胞总数，诱导食欲下降，从而导致体重减轻。GLP-1R属于G蛋白偶联受体(GPCRs)家族。这些受体存在于许多不同类型的细胞中，通常位于细胞的质膜上，因为它们可以检测到来自细胞外的激动剂形式的信号并被激活，在细胞内发送这些信号并产生细胞反应。一旦被激活，这些受体就会被重新定位到细胞中的不同细胞器，这种现象被称为运输，在这种现象中，它们被分类，要么被降解，从而终止信号，要么被循环进行另一轮激活，或者被送到特定的位置，在那里它们可以从细胞内部发出信号。因此，受体转运具有控制GLP-1R活性的潜力，但GLP-1R在胰岛β细胞中的转运尚未得到深入研究。因此，我建议使用最先进的高分辨率显微镜技术来研究GLP-1R在胰腺β细胞中的转运。我将通过操纵细胞中候选蛋白质的水平并分析对GLP-1R贩运的任何影响来确定规范这种贩运的主要参与者。我还将调查人类疾病的小鼠模型中是否存在贩运缺陷。此外，我将测量受体对细胞内信号的激活，并确定是否可以通过操纵GLP-1R贩运来改变这一点。我还将通过测量细胞存活和增殖水平以及它们分泌的胰岛素量来评估β细胞反应的任何差异。最后，我将评估一些GLP-1R激动剂引发的转运类型，这些激动剂目前正在作为新的糖尿病治疗药物开发，并且已知它们在胰腺β细胞中产生的信号类型不同。这些研究将确定能够调节β细胞中GLP-1R转运的基本新机制，以及这些机制如何影响受体产生的信号类型。他们还将确定在调节受体对胰岛素分泌、β细胞存活和增殖的已知影响方面的重要性，并可能为开发改进的2型糖尿病治疗方法开辟新的途径，这些方法也可能用于肥胖症的治疗。

Type 2 diabetes and obesity are two interconnected major public health problems, due to their epidemic proportions and association with adverse consequences such as cardiovascular disease and cancer. Patients with type 2 diabetes often experience pancreatic beta cell failure leading to reduced production and secretion of insulin. Glucagon-like peptide-1 receptor (GLP-1R) agonists are a new class of drugs for the treatment of type 2 diabetes that activate the GLP-1R, which in turn stimulates the release of insulin from beta cells in the pancreas, with better control of blood glucose levels than other therapies, while at the same time increasing the total number of beta cells and inducing a reduction in appetite leading to weight loss.GLP-1R belongs to a family of receptors known as G protein-coupled receptors (GPCRs). These receptors exist in many different types of cells, and are normally localised at the plasma membrane of cells were they can detect signals in the form of agonists from outside the cell and get activated, sending these signals inside the cell and generating a cellular response. Once activated, these receptors are relocated to different organelles in the cell in a phenomenon called trafficking, where they are sorted to either be degraded so the signal is terminated, recycled for another round of activation, or sent to specific locations where they can signal from inside the cell. Receptor trafficking has therefore the potential to control the activity of GLP-1R, but the trafficking of GLP-1R in pancreatic beta cells has not been studied in depth. I therefore propose to study the trafficking of GLP-1R in pancreatic beta cells using state-of-the-art high-resolution microscopy techniques. I will identify the main players that regulate this trafficking by manipulating the levels of candidate proteins in the cell and analysing any effects on GLP-1R trafficking. I will also investigate the presence of trafficking defects in mouse models of the human disease. Additionally, I will measure the activation of signals in the cell by the receptor, and I will establish whether this can be modified by the manipulation of GLP-1R trafficking. I will also evaluate any differences in the response of beta cells by measuring cell survival and proliferation levels as well as the amount of insulin they secrete. Finally, I will assess the type of trafficking elicited by a number of GLP-1R agonists which are currently being developed as new diabetes therapies, and which are known to have differences in the type of signals that they generate in pancreatic beta cells.These studies will identify fundamental new mechanisms capable of regulating GLP-1R trafficking in the beta cell, and how these affect the type of signals being generated by the receptor. They will also establish the importance of trafficking in the regulation of the known effects of the receptor on insulin secretion, survival and proliferation of beta cells, and might open new avenues for the development of improved therapy approaches for type 2 diabetes that might also be of use for the treatment of obesity.