This research proposed in this revised submission continues to have the broad goal to elucidate the cellular mechanisms associated with pancreatic islet beta cell destruction in autoimmune diabetes. Important observations relevant to the performance of this research are centered around the well characterized effects of IL-1 on islet beta cell function. IL-1 inhibits insulin secretion and targets iron-sulfur centers of mitochondrial enzymes. NO is an effector molecule produced by IL-1 induced iNOS expression by beta cells. INF gamma reduces the concentration of IL-1 required to stimulate iNOS expression by islets and is associated with an increased stability of iNOS mRNA. In the absence of IL-1 IFN gamma does not modulate beta cell function.
Specific aim 1 will elucidate the cellular signaling mechanisms required for IL-1 induced iNOS expression by beta cells and determine the mechanism by which IFN gamma primes for and potentiates IL-1 induced iNOS expression.
This aim i s based on the observations by the P.I. that IL-1 selectively stimulates inducible nitric oxide synthase (iNOS) expression by beta cells and that IFNgamma primes for and potentiates IL-1 induced iNOS expression. Therefore, cytokine induced iNOS expression and consequent production of high levels of NO is one mechanism of beta cell destruction.
Specific aim 2 will determine the cellular source of IL-1, the isoforms of IL-1, the mechanisms controlling intra-islet release of IL-1 and the effects of intra-islet release on beta cell function.
This aim i s directed to testing the hypothesis that intra-islet macrophage activation mediates the initial events leading to islet beta cell destruction.
Specific aim 3 will determine the cellular sources of iNOS and COX-2 (COX catalyzes the first reaction in the biosynthetic pathway responsible for the production of prostaglandins. COX 2 is inducible, IL-1 induces it and iNOS stimulates its activity), whether NO activates COX-2 and whether COX-2 and iNOS participate in islet inflammation and beta cell damage. A major goal of this aim is to test the hypothesis that proinflammatory and destructive actions of NO directly participate in islet inflammation and B cell damage in the NOD mouse model of autoimmune diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052194-03
Application #
6138047
Study Section
Metabolism Study Section (MET)
Program Officer
Akolkar, Beena
Project Start
1998-01-01
Project End
2002-12-31
Budget Start
2000-01-01
Budget End
2000-12-31
Support Year
3
Fiscal Year
2000
Total Cost
$215,373
Indirect Cost
Name
Saint Louis University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Baldwin, Aaron C; Naatz, Aaron; Bohnsack, Richard N et al. (2018) Cation-Independent Mannose 6-Phosphate Receptor Deficiency Enhances ?-Cell Susceptibility to Palmitate. Mol Cell Biol 38:
Kropp, Erin M; Broniowska, Katarzyna A; Waas, Matthew et al. (2017) Cardiomyocyte Differentiation Promotes Cell Survival During Nicotinamide Phosphoribosyltransferase Inhibition Through Increased Maintenance of Cellular Energy Stores. Stem Cells Transl Med 6:1191-1201
Schwab, Andrew J; Sison, Samantha L; Meade, Michael R et al. (2017) Decreased Sirtuin Deacetylase Activity in LRRK2 G2019S iPSC-Derived Dopaminergic Neurons. Stem Cell Reports 9:1839-1852
Hye Khan, Md Abdul; Hwang, Sung Hee; Sharma, Amit et al. (2016) A dual COX-2/sEH inhibitor improves the metabolic profile and reduces kidney injury in Zucker diabetic fatty rat. Prostaglandins Other Lipid Mediat 125:40-7
Oleson, Bryndon J; Broniowska, Katarzyna A; Naatz, Aaron et al. (2016) Nitric Oxide Suppresses ?-Cell Apoptosis by Inhibiting the DNA Damage Response. Mol Cell Biol 36:2067-77
Samson, Willis K; Stein, Lauren M; Elrick, Mollisa et al. (2016) Hypoglycemia unawareness prevention: Targeting glucagon production. Physiol Behav 162:147-50
Elrick, Mollisa M; Samson, Willis K; Corbett, John A et al. (2016) Neuronostatin acts via GPR107 to increase cAMP-independent PKA phosphorylation and proglucagon mRNA accumulation in pancreatic ?-cells. Am J Physiol Regul Integr Comp Physiol 310:R143-55
Shaheen, Zachary R; Corbett, John A (2015) Macrophage Expression of Inflammatory Genes in Response to EMCV Infection. Biomolecules 5:1938-54
Broniowska, Katarzyna A; Mathews, Clayton E; Corbett, John A (2015) Reply to Gurgul-Convey and Lenzen: Cytokines, nitric oxide, and ?-cells. J Biol Chem 290:10571
Shaheen, Zachary R; Naatz, Aaron; Corbett, John A (2015) CCR5-Dependent Activation of mTORC1 Regulates Translation of Inducible NO Synthase and COX-2 during Encephalomyocarditis Virus Infection. J Immunol 195:4406-14

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