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You searched for subject:(PERK eIF2alpha kinase). One record found.

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Penn State University

1. Wang, Rong. PERK eIF2alpha kinase regulates cell proliferation, insulin synthesis and secretion in pancreatic beta cells.

Degree: 2014, Penn State University

Insulin synthesis and secretion, as well as cell proliferation are under tight regulation in pancreatic β-cells to maintain glucose homeostasis. Dysfunction in any of these aspects leads to development of diabetes. PERK (EIF2AK3) is essential for normal development and function of the insulin-secreting β-cell. Genetic ablation of PERK in humans and mice results in permanent neonatal diabetes featuring insufficient β-cell mass, impaired insulin synthesis and ablated insulin secretion. However, previous attempts to identify the primary functions of PERK were confounded by those severe abnormalities within PERK-deficient β-cells. Here, I used a newly developed and highly specific inhibitor of PERK to determine the immediate effects of acute PERK activity inhibition. Stimulated subcellular Ca2+ signaling and insulin secretion in human and rodent β-cells was found to be rapidly reduced as a consequence of acute inhibition of PERK. These PERK-dependent dysfunctions stem from alterations in store-operated Ca2+ entry, sarcoplasmic-endoplasmic reticulum Ca2+ ATPase activity, and possibly some of the transient receptor potential channels. I also found that PERK regulates calcineurin, and pharmacological inhibition of calcineurin results in similar defects on stimulus-secretion coupling. My findings by using PERK inhibitor demonstrate that PERK acutely regulates β-cell Ca2+ signaling and insulin secretion. In addition, I used an alternative strategy to identify the primary functions of PERK by examining mice with one copy of the loss-of function Perk mutation (Perk heterozygous mice). Longitudinal studies were conducted to assess serum glucose and insulin, intracellular insulin synthesis and storage, insulin secretion, and β-cell proliferation in Perk heterozygous mice. I found that Perk heterozygous mice first exhibited elevated proinsulin synthesis, changes in ER chaperone expression, and enhanced insulin secretion during neonatal and juvenile development, followed by enhanced β-cell proliferation and a substantial increase in β-cell mass at the adult stage. These effects of Perk heterozygosity are opposite to what has been learned from previously studies using Perk knockout mice and therefore suggest an inverted U-shaped dose effect on insulin production and secretion with half-dosage (Perk heterozygotes) defining the maximum. Moreover, because commonly used sensitive markers for ER stress were not differentially expressed in Perk heterozygous mice, these PERK-dependent differences are not likely to entail the well-known function of PERK in ER stress response. Taken together my thesis work suggests that PERK has two major functions in the pancreatic β-cells: 1) acutely regulating insulin secretion through modulation of Ca2+ dynamics in a calcineurin-dependent pathway; and 2) impacting proinsulin folding and quality control in a longer-term through modulation of ER chaperone expression. These two major functions of PERK coordinate with each other and influence whole-body insulin production and glucose… Advisors/Committee Members: Douglas Cavener, Dissertation Advisor/Co-Advisor, Zhi Chun Lai, Committee Chair/Co-Chair, Richard W Ordway, Committee Member, Gong Chen, Committee Member, Melissa Rolls, Committee Member.

Subjects/Keywords: PERK eIF2alpha kinase; Ca2+ dynamics; insulin secretion; insulin biosynthesis; diabetes; ER stress; beta cell proliferation

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APA (6th Edition):

Wang, R. (2014). PERK eIF2alpha kinase regulates cell proliferation, insulin synthesis and secretion in pancreatic beta cells. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/21417

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Wang, Rong. “PERK eIF2alpha kinase regulates cell proliferation, insulin synthesis and secretion in pancreatic beta cells.” 2014. Thesis, Penn State University. Accessed April 14, 2021. https://submit-etda.libraries.psu.edu/catalog/21417.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Wang, Rong. “PERK eIF2alpha kinase regulates cell proliferation, insulin synthesis and secretion in pancreatic beta cells.” 2014. Web. 14 Apr 2021.

Vancouver:

Wang R. PERK eIF2alpha kinase regulates cell proliferation, insulin synthesis and secretion in pancreatic beta cells. [Internet] [Thesis]. Penn State University; 2014. [cited 2021 Apr 14]. Available from: https://submit-etda.libraries.psu.edu/catalog/21417.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Wang R. PERK eIF2alpha kinase regulates cell proliferation, insulin synthesis and secretion in pancreatic beta cells. [Thesis]. Penn State University; 2014. Available from: https://submit-etda.libraries.psu.edu/catalog/21417

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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