Analyzing the MafB transcription factor in islet beta cell formation and function

描述(申请人提供)：糖尿病患者的葡萄糖稳态失衡是由分泌胰岛素的胰岛细胞丢失或功能障碍引起的。人们正在共同努力了解细胞形成和功能背后的分子程序，以提供对糖尿病治疗策略的治疗洞察。这些研究表明，MafA和MafB转录因子是胰岛素和胰升糖素转录的关键调节因子。MafA仅在胰岛素产生细胞中发现，无论是在发育过程中还是在成人中，而MafB在分化的a细胞和？细胞中表达，然后在出生后局限于胰岛a细胞。由于MafB-/-小鼠在发育过程中产生的胰岛素+和胰升糖素+细胞较少，因此MafB对a细胞和？细胞的分化是必不可少的。相比之下，在全部Mafa基因敲除的动物中，胰岛细胞的形成是正常的，尽管成年后这些动物会出现细胞功能障碍和糖尿病。我们认为，MafB部分通过调节Pdx1、GLUT2和胰岛素转录来补偿细胞发育过程中MafA的丢失。我们的结果还表明，对成体细胞功能至关重要的基因首先由MafB在胚胎中控制，然后在出生后由MafA控制。我们将致力于确定MafB调控的基因如何影响胰岛细胞。这些知识可能对制定预防(或减少)糖尿病患者细胞功能障碍的治疗策略具有重要价值。与公共卫生相关：现在，相当大的努力集中在试图开发治疗方法来改善糖尿病患者的细胞功能。我认为，最终的成功将需要从根本上了解调控因素，这些因素是控制与功能细胞形成相关的专门遗传程序所必需的。我们已经确定了一种名为MafB的蛋白质，它在成年胰岛细胞功能所需的胰腺器官形成过程中控制基因的表达，并将在这里努力获得对其在这些过程中的重要性的完整看法。

DESCRIPTION (provided by applicant): The imbalance in glucose homeostasis in diabetic patients is caused by loss or dysfunction of insulin secreting pancreatic islet ¿ cells. A concerted effort is being made to understand the molecular programs underlying ¿ cell formation and function to provide therapeutic insight into diabetes treatment strategies. From these studies, the MafA and MafB transcription factors have been shown to be key regulators of Insulin and Glucagon transcription. MafA is found exclusively in insulin producing cells, both during development and in the adult, whereas MafB is expressed in differentiating a and ¿ cells and then becomes restricted to islet a cells postnatally. MafB is essential for a and ¿ cell differentiation, as MafB-/- mice produce fewer insulin+ and glucagon+ cells during development. In contrast, islet cell formation is normal in a total MafA knock out, although the animals develop ¿ cell dysfunction and diabetes as adults. We believe that MafB compensates for the loss of MafA during ¿ cell development, in part through regulation of Pdx1, GLUT2, and Insulin transcription. Our results also indicate that genes essential to adult ¿ cell function are first controlled by MafB embryonically and then by MafA postnatally. We will work towards defining how MafB regulated genes impact islet ¿ cells. This knowledge will likely be of great value in generating therapeutic strategies to prevent (or reduce) ¿ cell dysfunction in diabetic patients. PUBLIC HEALTH RELEVANCE: Considerable effort is now focused on trying to develop therapeutics to improve ¿ cell function in diabetic patients. I believe that ultimate success will require a fundamental understanding of the regulatory factors that are required for controlling the specialized genetic programs associated with the formation of functional ¿ cells. We have identified a protein, termed MafB, which controls expression of genes during pancreas organogenesis required for adult islet ¿ cell function, and will work here towards obtaining a complete perspective on its importance in these processes.