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