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

描述（由申请人提供）：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的损失或功能障碍引起的。目前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见解。从这些研究中，MafA和MafB转录因子已被证明是胰岛素和胰高血糖素转录的关键调节因子。MafA仅在发育期间和成人中的胰岛素产生细胞中发现，而MafB在分化中的α和β细胞中表达，然后在出生后局限于胰岛α细胞。MafB对α和β细胞分化至关重要，因为MafB-/-小鼠在发育过程中产生较少的胰岛素+和胰高血糖素+细胞。相比之下，在MafA基因敲除的情况下，胰岛细胞的形成是正常的，尽管动物成年后会出现细胞功能障碍和糖尿病。我们认为MafB在细胞发育过程中部分通过调节Pdx 1，GLUT 2和胰岛素转录来补偿MafA的损失。我们的研究结果还表明，成人细胞功能所必需的基因首先由MafB胚胎控制，然后由MafA出生后。我们将致力于确定MafB调控基因如何影响胰岛细胞。这些知识可能在产生预防（或减少）糖尿病患者细胞功能障碍的治疗策略方面具有重要价值。公共卫生相关性：现在相当大的努力集中在试图开发治疗方法，以改善糖尿病患者的细胞功能。我相信，最终的成功将需要对控制与功能性细胞形成相关的专门遗传程序所需的调节因子有基本的了解。我们已经确定了一种蛋白质，称为MafB，它控制成人胰岛细胞功能所需的胰腺器官形成过程中的基因表达，并将在这里工作，以获得其在这些过程中的重要性的完整观点。

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.