Hypusine as a nutrient-sensing modulator of eIF5A function in β cells

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PROJECT SUMMARY: This application is a proposal to train a predoctoral student with a passion for studying nutritional regulation of metabolic disease. I will conduct research in the laboratory of Dr. R. Mirmira at the University of Chicago and will engage in career development activities to foster my aim to lead an academic research program as a principal investigator. Career development activities will include formal training in the art of scientific writing, opportunities for presentation at regional and national meetings, and writing opportunities that include manuscripts for publication. The majority of time will be spent in primary research at the bench involving studies related to diabetes, an increasingly prevalent threat to public health in the United States. The research program will focus on the biology of the islet β cell, which is known to be defective in virtually all forms of diabetes. Understanding the stimuli and mechanisms of endogenous β cell mass expansion has powerful therapeutic potential, and the proposal will study a rare and unusual modification known as hypusination. Deoxyhypusine synthase (DHPS) catalyzes the formation of the rare amino acid hypusine on eIF5A, activating its known function as a translation factor. DHPS deficiency in the β cell results in mice that exhibit impaired β cell adaptive proliferation, emphasizing the role for this unusual modification in normal β cell responses. However, deletion of DHPS in this model also increases the prevalence of un-hypusinated eIF5A (eIF5ALys), and it remains unknown if the phenotype observed might emanate from the presence of this form as opposed to the absence of the hypusinated form of the factor (eIF5AHyp). My preliminary data indicate an interaction between eIF5ALys and the kinase Gcn2, which phosphorylates and inhibits the translation factor eIF2-α during amino acid scarcity. Association between Gcn2 and eIF5ALys suggests a possible role in negative translation regulation and nutrient homeostasis for this uncharacterized isoform. I hypothesize that eIF5ALys functions as a negative regulator of mRNA translation and its accumulation in the islet β cell suppresses adaptive β cell proliferation. To investigate this hypothesis, I will achieve the following two specific aims: (1) Investigate the metabolic effects of eIF5ALys accumulation in β cells in vivo, and (2) Define the molecular mechanisms governing eIF5ALys regulation of protein translation in β cells. This proposal will target a gap of knowledge in the literature regarding the unmodified form of eIF5A and elaborate on the therapeutic potential of modulating the hypusination for β cell proliferation in diabetes. Completing these studies will reinforce skills in data interpretation, research independence, and project management in me as a young investigator so that I can make future independent and impactful contributions to science.