? ? There is growing evidence that chronic exposure of humans to inorganic arsenic, a potent environmental oxidative stressor, is associated with the incidence of Type 2 diabetes. In contrast to what has been a prevailing beneficial view of antioxidants in preventing pancreatic ?-cell dysfunction in diabetes, this project proposes that in response to arsenic exposure, transcription factor Nrf2-mediated adaptive induction of endogenous antioxidant enzymes plays paradoxical roles in ?-cell function. The investigators hypothesize that, on the one hand, Nrf2-mediated antioxidant response blunts glucose-triggered `ROS signaling' that plays an important role in glucose-stimulated insulin secretion (GSIS); on the other hand, the response protects ?-cells from oxidative damage and subsequent apoptosis/necrosis. The investigators propose three specific aims: (1) Test the hypothesis that induction of antioxidant enzymes in response to arsenic exposure and related oxidative stress impedes glucose-triggered `ROS signaling' and thus GSIS; (2) Test the hypothesis in silico that adaptive induction of antioxidant enzymes in response to chronic oxidative stress impedes `ROS signaling', and explore intervention approaches that can improve `ROS signaling'; (3) Test the hypothesis that Nrf2-mediated antioxidant response is critical for protecting ?-cells from oxidative damage and apoptosis/necrosis induced by arsenic and/or glucose toxicity. The integrated wet-lab and computational approaches will allow to: (1) understand how environmental arsenic exposure impairs ?-cell function; (2) characterize the quantitative nature of the effect of arsenic-induced oxidative stress on `ROS signaling' that is involved in GSIS; (3) distinguish the specific roles of Nrf2 and its target antioxidant enzymes in `ROS signaling' and ?-cell function; and (4) identify novel targets and approaches to modulate insulin secretion and protect ?-cells from oxidative damage. This project will investigate the pathogenic mechanisms of Type 2 Diabetes caused by environmental arsenic exposure. The results may enable new therapeutic managements and preventive strategies for arsenic or other environmental oxidative stress-associated diabetes. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES016005-01A1
Application #
7540646
Study Section
Special Emphasis Panel (ZES1-JAB-C (R2))
Program Officer
Heindel, Jerrold
Project Start
2008-09-12
Project End
2013-05-31
Budget Start
2008-09-12
Budget End
2009-05-31
Support Year
1
Fiscal Year
2008
Total Cost
$570,068
Indirect Cost
Name
The Hamner Institutes
Department
Type
DUNS #
040052250
City
Research Triangle Park
State
NC
Country
United States
Zip Code
27709
Chen, Yanyan; Xu, Yuanyuan; Zheng, Hongzhi et al. (2016) The role of nuclear factor E2-Related factor 2 and uncoupling protein 2 in glutathione metabolism: Evidence from an in vivo gene knockout study. Biochem Biophys Res Commun 478:87-92
Peng, Hui; Wang, Huihui; Xue, Peng et al. (2016) Suppression of NRF2-ARE activity sensitizes chemotherapeutic agent-induced cytotoxicity in human acute monocytic leukemia cells. Toxicol Appl Pharmacol 292:1-7
Zhang, Qiang; Bhattacharya, Sudin; Pi, Jingbo et al. (2015) Adaptive Posttranslational Control in Cellular Stress Response Pathways and Its Relationship to Toxicity Testing and Safety Assessment. Toxicol Sci 147:302-16
Zheng, Hongzhi; Fu, Jingqi; Xue, Peng et al. (2015) CNC-bZIP protein Nrf1-dependent regulation of glucose-stimulated insulin secretion. Antioxid Redox Signal 22:819-31
Chen, Yanyan; Xue, Peng; Hou, Yongyong et al. (2013) Isoniazid suppresses antioxidant response element activities and impairs adipogenesis in mouse and human preadipocytes. Toxicol Appl Pharmacol 273:435-41
Lv, Peng; Xue, Peng; Dong, Jian et al. (2013) Keap1 silencing boosts lipopolysaccharide-induced transcription of interleukin 6 via activation of nuclear factor ?B in macrophages. Toxicol Appl Pharmacol 272:697-702
Zhang, Qiang; Bhattacharya, Sudin; Andersen, Melvin E (2013) Ultrasensitive response motifs: basic amplifiers in molecular signalling networks. Open Biol 3:130031
Xue, Peng; Hou, Yongyong; Chen, Yanyan et al. (2013) Adipose deficiency of Nrf2 in ob/ob mice results in severe metabolic syndrome. Diabetes 62:845-54
Hou, Yongyong; Xue, Peng; Woods, Courtney G et al. (2013) Association between arsenic suppression of adipogenesis and induction of CHOP10 via the endoplasmic reticulum stress response. Environ Health Perspect 121:237-43
Fu, Jingqi; Zhang, Qiang; Woods, Courtney G et al. (2013) Divergent effects of sulforaphane on basal and glucose-stimulated insulin secretion in ?-cells: role of reactive oxygen species and induction of endogenous antioxidants. Pharm Res 30:2248-59

Showing the most recent 10 out of 28 publications