A novel, beta cell specific regulator of the insulin promoter

描述(申请人提供)：胰岛β细胞是人体唯一的胰岛素来源。β细胞的衰竭或破坏分别导致2型糖尿病和1型糖尿病。通过全基因组RNA干扰筛选，我们在胰岛β细胞中发现了一种新的胰岛素表达调控因子。有趣的是，与非胰岛组织相比，该基因似乎在β细胞中高度丰富，使其成为一个有吸引力的候选基因。这样做的第一个目的是 R03建议研究小鼠对该基因的敲除。具体地说，将在缺乏该基因的β细胞表达的小鼠中测量胰岛素表达、葡萄糖耐量、胰岛素耐量和胰岛素分泌。第二个目的是询问在人类胰岛中敲除人类该基因的同源基因是否也会影响胰岛素的表达和胰岛素的分泌。为了做到这一点，针对该基因的小发夹RNA将使用腺病毒传递到人类胰岛。然后，将测量胰岛素启动子活性和葡萄糖刺激的胰岛素分泌。这项应用的目标是提供关键的体内数据，以支持R01在该基因在β细胞功能中的详细机制方面的应用。

DESCRIPTION (provided by applicant): The pancreatic beta cell is the body's only source of insulin. The failure or destruction of the beta cell results in type 2 and type 1 diabetes respectively. We identified a novel regulator of insulin expression in the pancreatic beta cell wit a whole genome RNA interference screen. Interestingly, this gene appears to be highly enriched in the beta cell versus non-islet tissues, making it an attractive candidate. The first aim of this R03 proposes to study the mouse knockout of this gene. Specifically, insulin expression, glucose tolerance, insulin tolerance, and insulin secretion will be measured in mice lacking beta cell expression of this gene. The second aim asks if knockdown of the human homolog of this gene in human islets also affects insulin expression and insulin secretion. To do this, small hairpin RNAs targeting this gene will be delivered into human islets using adenovirus. Then, insulin promoter activity and glucose stimulated insulin secretion will be measured. The goal of this application is to provide critical in vivo data to support an R01 application on the detailed mechanism of this gene in beta cell function.