Identification of Genes and Compounds That Control Beta Cell Replication

描述（由申请人提供）：本提案中的研究将应用遗传，细胞生物学和化学筛选方法，目标是确定2型糖尿病（T2D）的新治疗方法，从而解决本资助计划的主题领域1和2。由于胰腺β细胞的相对缺乏，T2D患者无法产生足够的胰岛素来控制血糖水平。如果能够增加T2D患者的β细胞数量，可以显著改善其血糖控制，从而延缓或预防慢性高血糖的破坏性后果。已经确定β细胞具有通过复制显著增加其数量的能力，这表明利用这种复制潜力作为T2D治疗途径的可能性。然而，具体控制β细胞复制的基因在很大程度上是未知的。同样，可以提高β细胞复制率的小分子也没有被描述。为了确定控制β细胞复制的基因，我们建议使用微阵列分析来比较活跃复制的β细胞群体与静止群体的转录谱。通过这种方式，我们将能够确定候选调控基因，其表达与复制状态呈正相关或负相关。同时，我们将在培养的胰岛上进行高通量小分子筛选，以确定可以在体外刺激β细胞复制速率的化合物。通过这两种分析确定的基因和化合物将在小鼠模型中进行测试，以确定它们在体内调节β细胞复制的能力。因此，本提案中的研究可能会导致识别新的治疗靶点和候选药物，用于治疗糖尿病。

DESCRIPTION (provided by applicant): The research in this proposal will apply genetic, cell biological and chemical screening approaches with the goal of identifying novel treatments for type 2 diabetes (T2D), thus addressing thematic areas 1 and 2 of this grants program. Due to a relative deficiency in pancreatic beta cells, T2D patients are unable to produce sufficient insulin to control their blood glucose levels. If the number of beta cells in T2D patients could be increased, their glycemic control could be significantly improved, thus delaying or preventing the devastating consequences of chronic hyperglycemia. It is well established that beta cells possess the capacity to dramatically increase their numbers by replication, suggesting the possibility of harnessing this replicative potential as a therapeutic avenue for T2D. However, genes that specifically control beta cell replication are largely unknown. Likewise, small molecules that can boost beta cell replication rates have not been described. To identify genes that control beta cell replication, we propose to use microarray analysis to compare the transcription profiles of actively replicating populations of beta cells to the profiles of quiescent populations. In this way, we will be able to identify candidate regulatory genes whose expression either positively or negatively correlates with replication status. In parallel, we will undertake a high-throughput small molecule screen on cultured pancreatic islets to identify compounds that can stimulate the rate of beta cell replication in vitro. Genes and compounds identified by these two analyses will then be tested in mouse models to determine their ability to regulate beta cell replication in vivo. Thus, the studies in this proposal are likely to lead to the identification of novel therapeutic targets and drug candidates for the treatment of diabetes. PUBLIC HEALTH RELEVANCE: The incidence of type 2 diabetes is rapidly increasing in the United States and worldwide. The negative impacts of long-term diabetes on a patient's health are significant, and carry with them a heavy financial burden. The therapies that will be developed as a result of the proposed research could be used to treat type 2 diabetes, and delay or prevent the devastating consequences of long-term disease. Thus, these therapies will both alleviate patient suffering while simultaneously reducing the financial costs of this disease.