PROJECT ABSTRACT
There is a massive prevalence of diabetes in the U.S. with 34.2 million having diabetes, and 88 million adults
with prediabetes. Type 1 diabetes results from the autoimmune destruction of the islet ß cell mediated in part by
ß-cell dysfunction prior to autoimmune attack. Polyamine and hypusine production are important for the
translation of a subset of RNAs involved in the unfolded protein response, ER stress, and cytokine response in
the ß cell. Our preliminary data suggests that the polyamine/hypusine pathway is involved in the translation of
proteins required for the response of the ß cell to inflammation. Inhibition of two rate limiting enzymes along the
polyamine/hypusine pathway, either genetically or with small molecule inhibitors, results in a decrease of ER
stress leading to protection from ß-cell death and ultimately type 1 diabetes. For this proposal we will use a
combination of mouse, and human models to understand how the polyamines and hypusine specifically alter the
ß cell’s response to stress. We propose to study the role of polyamines and hypusine in specific mRNA translation
of proteins that are important to the maladaptive response of ß-cell ER stress and hypothesis that polyamine
depletion leads to ER stress resolution, preserved ß-cell function, and ultimately reduced T1D pathogenesis. To
test this hypothesis, we propose the following aims:
Aim 1: Interrogate the molecular mechanisms by which the polyamine/hypusine pathway contributes to ß-cell
dysfunction and death.
Aim 2: Determine the role of ß cell polyamine/hypusine pathway during autoimmunity and the development of
T1D.
Aim 3: Assess the efficacy of treatment with polyamine/hypusine blockade.
The primary impact of this proposal is the identification of mechanisms of the polyamine/hypusine pathway in ß
cells during the diabetes pathogenesis.