PROJECT SUMMARY/ABSTRACT Following developmental specification, pancreatic beta cells adapt to changes in the postnatal environment through functional maturation. They gain glucose-responsive insulin secretion, and gradually refine it by increasing the glucose threshold for secretion and expanding secretory capacity. While factors promoting beta cell maturation have been described, the underlying molecular mechanisms and their physiological triggers remain unclear. New insights into how beta cells acquire their mature phenotype are needed to develop efforts to curb loss of this phenotype during the onset of type 1 and type 2 diabetes, and to generate functionally mature beta cells from stem cells that can be used as transplantation therapy. The transcription factor Dec1 is a modulator of the circadian clock mechanism that is specifically activated during postnatal beta cell maturation. Dec1 binds promoter/enhancers of genes encoding key mediators of mature glucose sensing and insulin secretion, and loss of Dec1 in beta cells renders mice diabetic due to physiologically immature islets. Dr. Alvarez proposes to investigate the molecular basis for these phenotypes, by 1) examining the impact of Dec1 loss on the epigenome, transcriptome, and proteome of single pancreatic beta cells, and 2) determining the functional partners and molecular mechanisms by which Dec1 modulates beta cell maturity. These innovative experiments complement Dr. Alvarez' prior skills while conferring new training in circadian live-animal studies and single-cell technologies. A world-class team of mentors and collaborators with leading experience in these methods and in beta cell, diabetes, and circadian physiology ensures exceptional guidance. In addition, a series of formal, structured didactic and experiential training activities aimed at fostering Dr. Alvarez' development as an independent investigator are proposed. In all, the proposed research and career development activities will be critical to Dr. Alvarez developing a new independent research program focused on linking circadian biology to beta cell physiology. Results from this research program will be important to identify and exploit therapeutic opportunities to manage, prevent, or even restore the loss of mature beta cell function in diabetic patients.

PROJECT NARRATIVE Circadian clocks tune insulin secretion to feeding-fasting cycles and disturbing them predisposes to diabetes, yet the underlying mechanisms remain obscure. This study proposes to investigate the control of beta-cell glucose responsiveness by the circadian clock modulator Dec1, with the goal of gaining new insights into the beta cell maturation process. Results from this research will illuminate opportunities for behavioral interventions or pharmacological targeting to manage, prevent, or even restore the loss of mature beta cell function in diabetic patients.