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 β cell mediated in part by β-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 β cell. Our preliminary data suggests that the polyamine/hypusine pathway is involved in the translation of proteins required for the response of the β 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 β-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 β 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 β-cell ER stress and hypothesis that polyamine depletion leads to ER stress resolution, preserved β-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 β-cell dysfunction and death. Aim 2: Determine the role of β 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 β cells during the diabetes pathogenesis.