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

Vanderbilt University, Nashville TN

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Abstract

DESCRIPTION (provided by applicant): The imbalance in glucose homeostasis in diabetic patients is caused by loss or dysfunction of insulin secreting pancreatic islet [unreadable] cells. A concerted effort is being made to understand the molecular programs underlying [unreadable] 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 [unreadable] cells and then becomes restricted to islet a cells postnatally. MafB is essential for a and [unreadable] 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 [unreadable] cell dysfunction and diabetes as adults. We believe that MafB compensates for the loss of MafA during [unreadable] cell development, in part through regulation of Pdx1, GLUT2, and Insulin transcription. Our results also indicate that genes essential to adult [unreadable] cell function are first controlled by MafB embryonically and then by MafA postnatally. We will work towards defining how MafB regulated genes impact islet [unreadable] cells. This knowledge will likely be of great value in generating therapeutic strategies to prevent (or reduce) [unreadable] cell dysfunction in diabetic patients. PUBLIC HEALTH RELEVANCE: Considerable effort is now focused on trying to develop therapeutics to improve [unreadable] 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 [unreadable] cells. We have identified a protein, termed MafB, which controls expression of genes during pancreas organogenesis required for adult islet [unreadable] cell function, and will work here towards obtaining a complete perspective on its importance in these processes.