The focus of this proposal is to investigate the role of the PERK eIF2a kinase (EIF2AK3) in regulating proinsulin trafficking and quality control in the endoplasmic reticulum. PERK is among a small set of genes identified in mice and humans that are so critically important to beta cell functions that loss of function mutations result in permanent neonatal diabetes due to insulin insufficiency. Moreover, mutations in Perk are the most common cause of consanguineous permanent neonatal diabetes in man. Our investigation of global and tissue-specific Perk KO mice led to the discovery that PERK is required for normal beta cell proliferation, proinsulin trafficking, and insulin secretion. However, the severity and magnitude of the beta cell defects seen when PERK expression is entirely absent makes the Perk KO unsuitable as the primary tool to discover the molecular and physiological functions of PERK in beta cells. We have chosen an alternative strategy whereby we will modulate PERK expression from 0.2 to 2-fold of normal levels and then investigate the acute effects on proinsulin trafficking and insulin secretion. A key assumption of this strategy is that more modest changes in expression can alter physiological outcomes. In support of this assumption we have already shown that reducing Perk gene dosage in half results in reduced blood glucose levels and ameliorates the progression of diabetes of the Akita insulin mutant mouse, whereas increasing Perk dosage above normal results in increased blood glucose levels and accelerates the progression of diabetes in Akita mice. We propose that PERK is required to regulate proinsulin quality control and trafficking in the endoplasmic reticulum as a function of the physiological demand for insulin. Hence our overall strategy is to test the this hypothesis by determining how PERK regulates quality control and trafficking of wildtype and Akita proinsulin, determine how PERK regulates ER chaperone and folding proteins underlying these functions, and determine how the regulation of PERK activity responds to normal changes in metabolism to mediate changes in proinsulin trafficking and insulin secretion.

Public Health Relevance

Over the past several decades the number of cases of diabetes mellitus has grown significantly and is now one of our nation's leading causes of death and disability. Insufficient insulin synthesis and secretion contributes to all forms of diabetes mellitus in humans, so understanding how these processes work is critical if we are to continue to help patients manage this disease and eventually find a cure. The aims of this proposal are to characterize how a key gene in regulating functions of the insulin-secreting beta cell controls the synthesis and secretion of insulin.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Appel, Michael C
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Pennsylvania State University
Schools of Arts and Sciences
University Park
United States
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Sowers, Carrie R; Wang, Rong; Bourne, Rebecca A et al. (2018) The protein kinase PERK/EIF2AK3 regulates proinsulin processing not via protein synthesis but by controlling endoplasmic reticulum chaperones. J Biol Chem 293:5134-5149
Zhu, Siying; Henninger, Keely; McGrath, Barbara C et al. (2016) PERK Regulates Working Memory and Protein Synthesis-Dependent Memory Flexibility. PLoS One 11:e0162766
Zhu, Siying; McGrath, Barbara C; Bai, Yuting et al. (2016) PERK regulates Gq protein-coupled intracellular Ca2+ dynamics in primary cortical neurons. Mol Brain 9:87
Wang, Rong; Munoz, Elyse E; Zhu, Siying et al. (2014) Perk gene dosage regulates glucose homeostasis by modulating pancreatic ?-cell functions. PLoS One 9:e99684
Xu, Xu; Hu, Jingjie; McGrath, Barbara C et al. (2013) GCN2 regulates the CCAAT enhancer binding protein beta and hepatic gluconeogenesis. Am J Physiol Endocrinol Metab 305:E1007-17
Wang, Rong; McGrath, Barbara C; Kopp, Richard F et al. (2013) Insulin secretion and Ca2+ dynamics in ?-cells are regulated by PERK (EIF2AK3) in concert with calcineurin. J Biol Chem 288:33824-36
Xu, Xu; Hu, Jingjie; McGrath, Barbara C et al. (2013) GCN2 in the brain programs PPAR?2 and triglyceride storage in the liver during perinatal development in response to maternal dietary fat. PLoS One 8:e75917
Saito, Atsushi; Ochiai, Kimiko; Kondo, Shinichi et al. (2011) Endoplasmic reticulum stress response mediated by the PERK-eIF2(alpha)-ATF4 pathway is involved in osteoblast differentiation induced by BMP2. J Biol Chem 286:4809-18
Xu, Xu; Gupta, Sounak; Hu, Wenli et al. (2011) Hyperthermia induces the ER stress pathway. PLoS One 6:e23740
Gupta, Sounak; McGrath, Barbara; Cavener, Douglas R (2010) PERK (EIF2AK3) regulates proinsulin trafficking and quality control in the secretory pathway. Diabetes 59:1937-47

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