Browsing by Author "May, Sarah C."

Now showing 1 - 4 of 4
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    Hypusinated and unhypusinated isoforms of the translation factor eIF5A exert distinct effects in models of pancreas development and function
    (Elsevier, 2025) Anderson, Cara M.; Kulkarni, Abhishek; Maier, Bernhard; Huang, Fei; Figatner, Kayla; Chakraborty, Advaita; Pratuangtham, Sarida; May, Sarah C.; Tersey, Sarah A.; Anderson, Ryan M.; Mirmira, Raghavendra G.; Medicine, School of Medicine
    Hypusination of eukaryotic translation initiation factor 5A (eIF5A) is essential for its role in translation elongation and termination. Although the function of hypusinated eIF5A (eIF5AHyp) in cellular proliferation is well characterized, the role of its unhypusinated form (eIF5ALys) remains unclear. We hypothesized that eIF5ALys exerts independent and negative effects on cellular replication and metabolism, distinct from the loss of eIF5AHyp. To test this hypothesis, we utilized zebrafish and mouse models with inducible knockdowns of deoxyhypusine synthase (DHPS) and eIF5A to investigate their roles in cellular growth. Gene expression analysis via RNA sequencing and morphometric measurements of pancreas and β-cell mass were performed to assess phenotypic changes and identify affected biological pathways. Loss of DHPS in zebrafish resulted in significant defects in pancreatic growth, accompanied by changes in gene expression related to mRNA translation, neurogenesis, and stress pathways. By contrast, knockdown of eIF5A had minimal impact on pancreas development, suggesting that the effects of DHPS loss are not solely because of the lack of eIF5AHyp. In mice, β-cell-specific deletion of DHPS impaired β-cell mass expansion and glucose tolerance, whereas eIF5A deletion had no statistically significant effects. These findings provide evidence for an independent role for eIF5ALys in regulating developmental and functional responses in pancreas health and disease.
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    Inhibition of the Eukaryotic Initiation Factor-2-α Kinase PERK Decreases Risk of Autoimmune Diabetes in Mice
    (bioRxiv, 2024-06-03) Muralidharan, Charanya; Huang, Fei; Enriquez, Jacob R.; Wang, Jiayi E.; Nelson, Jennifer B.; Nargis, Titli; May, Sarah C.; Chakraborty, Advaita; Figatner, Kayla T.; Navitskaya, Svetlana; Anderson, Cara M.; Calvo, Veronica; Surguladze, David; Mulvihill, Mark J.; Yi, Xiaoyan; Sarkar, Soumyadeep; Oakes, Scott A.; Webb-Robertson, Bobbie-Jo M.; Sims, Emily K.; Staschke, Kirk A.; Eizirik, Decio L.; Nakayasu, Ernesto S.; Stokes, Michael E.; Tersey, Sarah A.; Mirmira, Raghavendra G.; Pediatrics, School of Medicine
    Preventing the onset of autoimmune type 1 diabetes (T1D) is feasible through pharmacological interventions that target molecular stress-responsive mechanisms. Cellular stresses, such as nutrient deficiency, viral infection, or unfolded proteins, trigger the integrated stress response (ISR), which curtails protein synthesis by phosphorylating eIF2α. In T1D, maladaptive unfolded protein response (UPR) in insulin-producing β cells renders these cells susceptible to autoimmunity. We show that inhibition of the eIF2α kinase PERK, a common component of the UPR and ISR, reverses the mRNA translation block in stressed human islets and delays the onset of diabetes, reduces islet inflammation, and preserves β cell mass in T1D-susceptible mice. Single-cell RNA sequencing of islets from PERK-inhibited mice shows reductions in the UPR and PERK signaling pathways and alterations in antigen processing and presentation pathways in β cells. Spatial proteomics of islets from these mice shows an increase in the immune checkpoint protein PD-L1 in β cells. Golgi membrane protein 1, whose levels increase following PERK inhibition in human islets and EndoC-βH1 human β cells, interacts with and stabilizes PD-L1. Collectively, our studies show that PERK activity enhances β cell immunogenicity, and inhibition of PERK may offer a strategy to prevent or delay the development of T1D.
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    Inhibition of the eukaryotic initiation factor-2α kinase PERK decreases risk of autoimmune diabetes in mice
    (American Society for Clinical Investigation, 2024-06-18) Muralidharan, Charanya; Huang, Fei; Enriquez, Jacob R.; Wang, Jiayi E.; Nelson, Jennifer B.; Nargis, Titli; May, Sarah C.; Chakraborty, Advaita; Figatner, Kayla T.; Navitskaya, Svetlana; Anderson, Cara M.; Calvo, Veronica; Surguladze, David; Mulvihill, Mark J.; Yi, Xiaoyan; Sarkar, Soumyadeep; Oakes, Scott A.; Webb-Robertson, Bobbie-Jo M.; Sims, Emily K.; Staschke, Kirk A.; Eizirik, Decio L.; Nakayasu, Ernesto S.; Stokes, Michael E.; Tersey, Sarah A.; Mirmira, Raghavendra G.; Pediatrics, School of Medicine
    Preventing the onset of autoimmune type 1 diabetes (T1D) is feasible through pharmacological interventions that target molecular stress–responsive mechanisms. Cellular stresses, such as nutrient deficiency, viral infection, or unfolded proteins, trigger the integrated stress response (ISR), which curtails protein synthesis by phosphorylating eukaryotic translation initiation factor-2α (eIF2α). In T1D, maladaptive unfolded protein response (UPR) in insulin-producing β cells renders these cells susceptible to autoimmunity. We found that inhibition of the eIF2α kinase PKR-like ER kinase (PERK), a common component of the UPR and ISR, reversed the mRNA translation block in stressed human islets and delayed the onset of diabetes, reduced islet inflammation, and preserved β cell mass in T1D-susceptible mice. Single-cell RNA-Seq of islets from PERK-inhibited mice showed reductions in the UPR and PERK signaling pathways and alterations in antigen-processing and presentation pathways in β cells. Spatial proteomics of islets from these mice showed an increase in the immune checkpoint protein programmed death-ligand 1 (PD-L1) in β cells. Golgi membrane protein 1, whose levels increased following PERK inhibition in human islets and EndoC-βH1 human β cells, interacted with and stabilized PD-L1. Collectively, our studies show that PERK activity enhances β cell immunogenicity and that inhibition of PERK may offer a strategy for preventing or delaying the development of T1D.
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    Non-Alcoholic Fatty Liver Disease: Translating Disease Mechanisms into Therapeutics Using Animal Models
    (MDPI, 2023-06-10) Basha, Amina; May, Sarah C.; Anderson, Ryan M.; Samala, Niharika; Mirmira, Raghavendra G.; Medicine, School of Medicine
    Nonalcoholic fatty liver disease (NAFLD) is a range of pathologies arising from fat accumulation in the liver in the absence of excess alcohol use or other causes of liver disease. Its complications include cirrhosis and liver failure, hepatocellular carcinoma, and eventual death. NAFLD is the most common cause of liver disease globally and is estimated to affect nearly one-third of individuals in the United States. Despite knowledge that the incidence and prevalence of NAFLD are increasing, the pathophysiology of the disease and its progression to cirrhosis remain insufficiently understood. The molecular pathogenesis of NAFLD involves insulin resistance, inflammation, oxidative stress, and endoplasmic reticulum stress. Better insight into these molecular pathways would allow for therapies that target specific stages of NAFLD. Preclinical animal models have aided in defining these mechanisms and have served as platforms for screening and testing of potential therapeutic approaches. In this review, we will discuss the cellular and molecular mechanisms thought to contribute to NAFLD, with a focus on the role of animal models in elucidating these mechanisms and in developing therapies.