Goal and Significance: Diabetes is a major health problem in the U.S. Many years of research indicate that beta cell destruction plays an important role in the pathogenesis and complication of diabetes. The goal of this proposal is to elucidate the roles of Activating Transcription Factor 3 (ATF3), a stress-inducible gene, in stress-induced signal transduction, beta cell dysfunction and destruction. The proposed research will test the following hypotheses. ? (1) Aim 1: To test the hypothesis that ATF3 is induced in beta cells by stress signals, at least in part, through the MAPK and NFkB pathways. Dominant negative molecules that block the activation of these pathways will be used to determine whether they could inhibit the induction of ATF3 in beta cells by stress signals (IL-1beta, hyperglycemia, and hyperlipidemia). In addition, constitutively active mutants that activate these pathways will be used to determine whether they could induce the expression of ATF3 in the absence of exogenously applied signals. ? (2) Aim 2: To test the hypothesis that expression of ATF3 leads to beta cell dysfunction, destruction and the development of diabetes. The mifepristone-inducible system will be used to generate transgenic mice expressing ATF3 in the islets in an inducible manner. These mice will be characterized for morphological, immunohistochemical and physiological parameters, and for islet cell death and cell proliferation. ? (3) Aim 3: To test the hypothesis that ATF3 plays an essential role in cytokine-induced beta cell dysfunction and destruction. Islet cells will be isolated from wild type (ATF3+/+), heterozygous (ATF3+/-) and homozygous (ATF3-/-) ATF3 knockout mice. Cells will be subjected to pro-inflammatory cytokines, nitric oxide donor S-nitroso glutathione (GSNO), or medium (control). Cell death will be analyzed at various time points to determine whether ATF3 is """"""""necessary"""""""" for stress signals to induce efficient beta cell death. In addition, islet functions will be analyzed to determine whether ATF3 is necessary for cytokines to induce beta cell dysfunction. For in vivo experiments, wild type and knockout mice will be injected with streptozotocin (STZ) to induce diabetes. Blood glucose levels and diabetes incidence will be analyzed to determine whether ATF3 knockout mice are less sensitive to STZ than wild type mice. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK059605-02
Application #
6726845
Study Section
Endocrinology Study Section (END)
Program Officer
Sato, Sheryl M
Project Start
2003-04-01
Project End
2007-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
2
Fiscal Year
2004
Total Cost
$285,783
Indirect Cost
Name
Ohio State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Wang, Hongbo; Jiang, Ming; Cui, Hongmei et al. (2012) The stress response mediator ATF3 represses androgen signaling by binding the androgen receptor. Mol Cell Biol 32:3190-202
Li, Dan; Yin, Xin; Zmuda, Erik J et al. (2008) The repression of IRS2 gene by ATF3, a stress-inducible gene, contributes to pancreatic beta-cell apoptosis. Diabetes 57:635-44
Khuu, Ciera H; Barrozo, Roberto M; Hai, Tsonwin et al. (2007) Activating transcription factor 3 (ATF3) represses the expression of CCL4 in murine macrophages. Mol Immunol 44:1598-605
Lu, Dan; Chen, Jingchun; Hai, Tsonwin (2007) The regulation of ATF3 gene expression by mitogen-activated protein kinases. Biochem J 401:559-67
Ameri, K; Hammond, E M; Culmsee, C et al. (2007) Induction of activating transcription factor 3 by anoxia is independent of p53 and the hypoxic HIF signalling pathway. Oncogene 26:284-9
Huo, Jeffrey S; McEachin, Richard C; Cui, Tracy Xiao et al. (2006) Profiles of growth hormone (GH)-regulated genes reveal time-dependent responses and identify a mechanism for regulation of activating transcription factor 3 by GH. J Biol Chem 281:4132-41
Lu, Dan; Wolfgang, Curt D; Hai, Tsonwin (2006) Activating transcription factor 3, a stress-inducible gene, suppresses Ras-stimulated tumorigenesis. J Biol Chem 281:10473-81
Jiang, Hao-Yuan; Wek, Sheree A; McGrath, Barbara C et al. (2004) Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response. Mol Cell Biol 24:1365-77
Hartman, Matthew G; Lu, Dan; Kim, Mi-Lyang et al. (2004) Role for activating transcription factor 3 in stress-induced beta-cell apoptosis. Mol Cell Biol 24:5721-32