Control of islet beta specific Pdx-1 and MafA transcription

In Years 1-5, Dr. Bass will use a combination of genetic, physiological, and genome-wide-based experiments to examine the interplay between Pdx1 and CLOCK/BMAL1 in β cell function and growth both prior to and following weaning. Dr. Bass’ team will test the hypothesis proposed in Aim 2 that induction of Pdx1 following weaning is necessary (i) to establish the cell-autonomous β cell circadian clock using circadian genetic reporter lines and live-cell luminometry and (ii) to enable self-sustained circadian transcription of genes important in signaling, insulin secretion and proliferation. Specifically, his group will use genetic bioluminescent monitoring in PER2::LUC transgenic reporter mice to determine the impact of reduced Pdx1 levels produced in the Pdx1ΔAreaIV β cells on properties of the core circadian oscillator, as well as on physiological outputs of clock. In addition, Dr. Bass will also use his expertise in genome-wide RNA-sequencing to examine precisely when rhythmic gene expression is induced after birth in wild type PER2::LUC expressing islets, and define the nature of the gene products produced during β cell maturation in relation to the importance of CLOCK/BMAL1 transcription factor activity in glucose-sensing, insulin secretion and cell proliferation.