Nr4a1 and the expansion of functional beta-cell mass - PROJECT SUMMARY/ABSTRACT Loss of functional beta cell mass is a hallmark of Type 1 and Type 2 diabetes. Increasing beta cell mass could be used as a treatment for diabetes. GLP1-R mediated signaling and inhibition of Dyrk1a activity are sufficient to increase functional beta cell mass. Nr4a1 is essential for beta cell proliferation and insulin secretion. Recent findings from our laboratory demonstrate that GLP1-R signaling results in upregulation of Nr4a1 in the beta cell. Similarly, Dyrk1a inhibition by Harmine, and Harmine derived compounds, results in upregulation of the Nfat family of transcription factors. We have shown that Nfatc2 and Nfac3 induce Nr4a1 expression, and that Nr4a1 deletion impairs Nfatc2 mediated beta cell proliferation. While these data suggest that Nr4a1 is essential for both the GLP-1R and Dyrk1a regulated beta cell proliferation pathways, and suggest an alternative target to expand functional beta cell mass, there are fundamental gaps in our understanding regarding Nr4a1 in these pathways, in terms of 1) the necessity of Nr4a1 in Exendin 4 and/or Harmine mediated beta cell proliferation, insulin secretion, and cell survival, 2) the effects of Exendin 4 and/or Harmine on Nr4a1 gene regulation in terms of binding partner interactions, genomic localization, and 3) how enhancing Nr4a1 expression and activity affects Exendin 4 and/or Harmine mediated beta cell proliferation. These gaps hinder the rationale design of targeted therapies to improve functional beta cell mass as a treatment for individuals with Type 1 and Type 2 diabetes. The long-term goal of our research is to develop strategies to improve beta cell function, proliferation and survival to improve patient outcomes. The overall objective of this proposal is to determine the role of Nr4a1 in the GLP1-R and Dyrk1a mediated pathways that expand functional beta cell mass. Our central hypothesis is that Nr4a1 is a key downstream that permits modulation of the GLP1-R and Dyrk1a pathways to enhance functional beta cell mass. Guided by our preliminary data, this hypothesis will be tested in the following specific aims: Aim 1: Determine the effect of Nr4a1 in GLP-1R and Dyrk1a mediated functional b-cell mass expansion. Aim 2: Determine the effect of Nr4a1 in the GLP-1R and Dyrk1a signaling pathway that leads to functional b-cell mass expansion. Aim 3: Determine the effect of Nr4a1 pharmacological modulation on GLP-1R and Dyrk1a mediated b- cell mass expansion. The proposal is innovative because it elucidates novel functions of Nr4a1 in these two proliferative pathways. The proposed research is significant because it fills fundamental gaps in our understanding of an understudied beta cell regulator, Nr4a1, its role in these critical pathways, and how its modulation can enhance functional beta cell mass.
