Understanding how exocrine-derived signals promote beta cell growth

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PROJECT SUMMARY The pancreas has commonly been considered two distinct organ systems wherein the endocrine compartment is responsible for hormone secretion and the exocrine compartment is responsible for the secretion of digestive enzymes. Although distinct, the endocrine and exocrine pancreas are functionally and structurally connected, working together to maintain metabolic homeostasis. Diseases of the exocrine can impact the endocrine; however, not all cases of exocrine disease result in endocrine dysfunction. For example, 50 - 80% of individuals with pancreatitis or exocrine insufficiency do not develop diabetes. This suggests that in certain instances the loss of exocrine pancreas may support the continued growth and function of the endocrine. Currently, there remains an incomplete understanding of the molecular pathways and communications that exist between cells of the endocrine and exocrine pancreas. Published studies and preliminary data from our lab reveal that hypusine biosynthesis plays a role in exocrine growth and function, which in turn may influence beta cell growth. Hypusine biosynthesis involves the post-translational modification of eukaryotic translation initiation factor 5A (eIF5A) by the enzyme deoxyhypusine synthase (DHPS) to form hypusinated eIF5A (eIF5AHyp), which functions in mRNA translation. Our studies demonstrate that loss of eIF5A in the developing pancreas causes a reduction in the synthesis of proteins involved in exocrine growth and function as well a loss of exocrine mass. Interestingly, the reduction in exocrine mass is concomitant with an increase in beta cell mass. Therefore, I hypothesize that the loss of exocrine mass, rather than altered mRNA translation, at the stage of exocrine differentiation drives beta cell growth due to the reduced amount of exocrine and exocrine- derived proteins. To test this hypothesis and determine if it is the loss of exocrine or the loss of eIF5A that stimulates beta cell expansion, I will perform experiments outline in two specific aims. Experiments in aim 1 will investigate how the absence of exocrine instructs beta cell growth in the embryonic and adult setting. Experiments in aim 2 will investigate how alterations in mRNA translation directly impacts exocrine growth and, resultantly, beta cell mass. In particular, my studies may identify exocrine-derived factors stimulate beta cell growth. Moreover, this award will provide critical holistic training encompassing five central objectives, which include: 1) building a strong background in techniques and concepts pertinent to diabetes research; 2) honing my scientific writing skills communication; 3) practicing my oral scientific communication; 4) enhancing my skills as a mentor; and 5) professional career development. My training plan also includes direct and enthusiastic support from my sponsor and co-sponsor, a thesis advisory committee composed of established NIH-funded investigators, and all of the resources/facilities in the IUPUI Department of Biology and the Center for Diabetes and Metabolic Diseases at the Indiana University School of Medicine, which will help me progress in my path to become an independent, diabetes-focused researcher.