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

描述（申请人提供）：糖尿病患者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，为糖尿病治疗策略提供治疗见解。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。无论是在发育过程中还是在成人中，MafA都只存在于产生胰岛素的细胞中，而MafB则在分化的a细胞和¿细胞中表达，然后在出生后仅限于胰岛a细胞。mab对a和¿细胞分化至关重要，因为mab -/-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，在完全MafA基因敲除的情况下，胰岛细胞的形成是正常的，尽管这些动物在成年后会出现细胞功能障碍和糖尿病。我们认为，在细胞发育过程中，MafB部分通过调节Pdx1、GLUT2和胰岛素转录来弥补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在胚胎时期由MafA控制，然后在出生后由MafA控制。我们将努力确定mab调控基因如何影响胰岛细胞。这一知识在制定预防（或减少）糖尿病患者细胞功能障碍的治疗策略方面可能具有很大的价值。公共卫生相关性：目前，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特殊遗传程序所需的调节因素有一个基本的了解。我们已经确定了一种称为MafB的蛋白质，它控制着成人胰岛细胞功能所需的胰腺器官发生过程中的基因表达，并将在这里工作，以获得其在这些过程中的重要性的完整视角。

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.