RNA Binding Proteins and Beta-cell Function

描述(申请人提供)：胰岛素的主要作用是葡萄糖稳态。内分泌胰岛的β细胞具有合成、储存和分泌胰岛素的功能。血糖升高刺激β细胞迅速部署预先形成的含有胰岛素的分泌颗粒，这些颗粒迅速经历调节的胞吐作用，将胰岛素释放到外周。为了恢复耗尽的细胞内胰岛素储存，葡萄糖还刺激胰岛素原、加工酶和其他一些未知的胞浆和分泌颗粒相关蛋白的生物合成。专门适应于β细胞的复杂代谢途径严格控制着这些步骤中的每一步。β细胞在1型和2型糖尿病的病理生理学中都起着关键作用。在过去的几年里，在差异显示和微阵列分析等全球细胞基因表达评估技术方面取得了巨大的进步。然而，不幸的是，这种技术经常导致产生高度复杂的数据集，这些数据集必须通过使用计算机模型来组织，以将表达的基因分组到可理解的模式中。因此，一个主要的组织方案对于将数据分析成功能上相关的分组将具有重要价值。细胞本身实际上提供了这样的组织结构。从所有基因复制的所有mRNA都通过一系列步骤进行处理，以修改、拼接、运输、降解、稳定、存储或翻译mRNA。本申请中描述的实验利用Ribonomics的新技术来快速分离聚集在功能相关路径中的独特的mRNA子集。正如我们将描述的，这项技术将使我们能够：1)更好地定义目前对β细胞中信号和代谢途径的理解；以及2)使我们能够识别先前未知的参与β细胞特定功能的成分。这些努力将产生一份治疗糖尿病的候选靶点清单。

DESCRIPTION (provided by applicant): The primary role of insulin is glucose homeostasis. The beta-cells of the endocrine pancreatic islets function to synthesize, store and secrete insulin. Elevated plasma glucose stimulates the beta-cell to acutely deploy preformed insulin-containing secretory granules that rapidly undergo regulated exocytosis, releasing insulin into the periphery. In order to restore the depleted intracellular stores of insulin, glucose also stimulates the biosynthesis of pro-insulin, processing enzymes, and a number of other unidentified cytosolic and secretory granule-associated proteins. Complex metabolic pathways that have been uniquely adapted to the beta-cell tightly regulate each of these steps. The beta-cells play a pivotal role in the pathophysiology of both Type 1 and Type 2 diabetes. During the past few years, dramatic improvements have been made in techniques for the global evaluation of cellular gene expression such as differential display and microarray analyses. Unfortunately however, such techniques often result in the production of highly complex data sets that must be organized through the use of computer models to group expressed genes into a comprehensible pattern. Therefore, a primary organizational scheme would be of great value to parse the data into functionally relevant groupings. The cell itself actually provides such an organizational structure. All mRNAs copied from all genes are processed through a series of steps to modify, splice, transport, degrade, stabilize, store, or translate the mRNAs. The experiments described in this application utilize Ribonomics' novel technology to rapidly isolate unique subsets of mRNAs that are clustered in functionally related pathways. As we will describe, this technology will allow us to; 1) better define the current understanding of signaling and metabolic pathways in the beta-cell; and 2) allow us to identify previously unknown components involved in beta-cell-specific functions. These efforts will produce a list of candidate therapeutic targets for the treatment of diabetes.