The major objective of this research program is to gain new insights into the molecular and cell biological mechanisms underlying the production and actions of insulin and related peptide hormones of the islets of Langerhans, including their genetic basis, evolutionary origins, and disorders in these processes, which may contribute to the pathophysiology of diabetes and/or other diseases. New projects and extensions of previous work are proposed as follows: (1) Studies on prohormone convertases PC1/PC3 (SPC3) and PC2 (SPC2), including further characterization of neuropeptide processing defects in mice with targeted disruptions of the PC1/PC3 and PC2 genes individually or in various crosses, (2) Studies on the role of the neuroendocrine protein proSAAS in normal proinsulin processing and on the mechanisms underlying ACTH hypersecretion in 7B2 null mice, (3) Studies on convertase subdomain structure and on transcriptional regulation of the PC 1/PC3 and PC2 genes, (4) Studies on prohormone structure in relation to their processing by convertases, (5) New studies on the identification and characterization of unique beta and alpha cell proteins and their roles in glucagon and insulin production and secretion, (6) Further studies on evolution of insulin and insulin/IGF receptor signaling systems, and (7) New studies to characterize the temporal course of changes in hepatic gene expression in diabetic animals in response to insulin. These studies should all contribute to improving our understanding of the genetic, evolutionary, and molecular biological mechanisms underlying islet hormone production and action and should contribute to a better understanding of the pathophysiology of diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK013914-34
Application #
6575813
Study Section
Metabolism Study Section (MET)
Program Officer
Haft, Carol R
Project Start
1974-11-01
Project End
2006-11-30
Budget Start
2002-12-20
Budget End
2003-11-30
Support Year
34
Fiscal Year
2003
Total Cost
$425,358
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Park, Soo-Young; Ludwig, Michael Z; Tamarina, Natalia A et al. (2014) Genetic complexity in a Drosophila model of diabetes-associated misfolded human proinsulin. Genetics 196:539-55
Menting, John G; Yang, Yanwu; Chan, Shu Jin et al. (2014) Protective hinge in insulin opens to enable its receptor engagement. Proc Natl Acad Sci U S A 111:E3395-404
He, Bin Z; Ludwig, Michael Z; Dickerson, Desiree A et al. (2014) Effect of genetic variation in a Drosophila model of diabetes-associated misfolded human proinsulin. Genetics 196:557-67
Menting, John G; Whittaker, Jonathan; Margetts, Mai B et al. (2013) How insulin engages its primary binding site on the insulin receptor. Nature 493:241-5
Stein, Jeffrey; Milewski, Wieslawa M; Dey, Arunangsu (2013) The negative cell cycle regulators, p27(Kip1), p18(Ink4c), and GSK-3, play critical role in maintaining quiescence of adult human pancreatic ?-cells and restrict their ability to proliferate. Islets 5:156-69
Steiner, Donald F (2011) On the discovery of precursor processing. Methods Mol Biol 768:3-11
Stein, Jeffrey; Milewski, Wieslawa M; Hara, Manami et al. (2011) GSK-3 inactivation or depletion promotes ýý-cell replication via down regulation of the CDK inhibitor, p27 (Kip1). Islets 3:21-34
Steiner, Donald F (2011) Adventures with insulin in the islets of Langerhans. J Biol Chem 286:17399-421
Smith, Brian J; Huang, Kun; Kong, Geoffrey et al. (2010) Structural resolution of a tandem hormone-binding element in the insulin receptor and its implications for design of peptide agonists. Proc Natl Acad Sci U S A 107:6771-6
Wardman, Jonathan H; Zhang, Xin; Gagnon, Sandra et al. (2010) Analysis of peptides in prohormone convertase 1/3 null mouse brain using quantitative peptidomics. J Neurochem 114:215-25

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