instnjctions): Recently, the modification of nuclear, mitochondrial, and cytoplasmic proteins by O-linked p-N- acetylglucosamine (0-GlcNAc) has emerged as a novel regulator of the stress response and cell survival. Numerous forms of cellular injury, including cardiac ischemic preconditioning (acute and prolonged), lead to elevated levels of 0-GlcNAc in both in vivo and in vitro models. Elevating 0-GlcNAcylation before, or immediately after, the induction of cellular injury is protective in models of ischemia reperfusion injury, as well as heat stress, oxidative stress, endoplasmic reticulum stress, hypoxia, and trauma hemorrhage. Together, these data suggest that 0-GlcNAc is a novel endogenous cardioprotective agent. However, the molecular mechanisms by which 0-GlcNAc regulates protein function leading to enhanced cell survival and cardioprotection have not been identified. The long term goal of this investigator, is to identify at a molecular level the mechanisms by which 0-GlcNAc promotes cell survival. The objective of this application is to: 1) Define the role(s) of 0-GlcNAc in mediating ischemic preconditioning. In order to characterize the mechanisms by which 0-GlcNAc leads to cardioprotection, proteins dynamically O-GlcNAc modified in response to ischemic-preconditioning will be identified and pathways that lead to enhanced 0-GlcNAcylation will be defined. 2) Elucidate the molecular mechanism(s) by which 0-GlcNAc regulates the process of autophagy leading to cardioprotection. To characterize the molecular mechanisms by which 0-GlcNAc protects cardiomyocytes via autophagy we will define: 1) the role of 0-GlcNAc in inducing autophagy during ischemic preconditioning;2) if enhanced autophagy is critical for 0- GlcNAc mediated cardioprotection;3) the identity of proteins involved directly in autophagy (or regulating autophagy) that are modified and regulated by 0-GlcNAc. Together, these studies will characterize a novel endogenous defense mechanism of the heart, highlighting new targets for the development of alternative strategies that enhance the hearts tolerance to ischemia reperfusion injury.

Public Health Relevance

The sugar 0-GlcNAc is a key component of the cellular stress response that enhances the ability of cells and tissues to survive ischemia reperfusion injury (for example, heart attack), but the mechanisms by which O- GlcNAc protects cells are unknown. Our goal is to understand how 0-GlcNAc promotes cell survival in a model of ischemia reperfusion injury at the molecular level, thus identifying new targets for the development of alternative strategies to enhance the heart's tolerance to ischemia reperfusion injury.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-H)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
United States
Zip Code
Zhu, Guangshuo; Groneberg, Dieter; Sikka, Gautam et al. (2015) Soluble guanylate cyclase is required for systemic vasodilation but not positive inotropy induced by nitroxyl in the mouse. Hypertension 65:385-92
Bullen, John W; Balsbaugh, Jeremy L; Chanda, Dipanjan et al. (2014) Cross-talk between two essential nutrient-sensitive enzymes: O-GlcNAc transferase (OGT) and AMP-activated protein kinase (AMPK). J Biol Chem 289:10592-606
Wang, Xiangchun; Chen, Jing; Li, Qing Kay et al. (2014) Overexpression of ? (1,6) fucosyltransferase associated with aggressive prostate cancer. Glycobiology 24:935-44
Hardivillé, Stéphan; Hart, Gerald W (2014) Nutrient regulation of signaling, transcription, and cell physiology by O-GlcNAcylation. Cell Metab 20:208-13
Hascall, Vincent C; Wang, Aimin; Tammi, Markku et al. (2014) The dynamic metabolism of hyaluronan regulates the cytosolic concentration of UDP-GlcNAc. Matrix Biol 35:14-7
Aiyetan, Paul; Zhang, Bai; Chen, Lily et al. (2014) M2Lite: An Open-source, Light-weight, Pluggable and Fast Proteome Discoverer MSF to mzIdentML Tool. J Bioinform 1:40-49
Harlan, Robert; Zhang, Hui (2014) Targeted proteomics: a bridge between discovery and validation. Expert Rev Proteomics 11:657-61
Seo, Kinya; Rainer, Peter P; Lee, Dong-Ik et al. (2014) Hyperactive adverse mechanical stress responses in dystrophic heart are coupled to transient receptor potential canonical 6 and blocked by cGMP-protein kinase G modulation. Circ Res 114:823-32
Liu, Yansheng; Chen, Jing; Sethi, Atul et al. (2014) Glycoproteomic analysis of prostate cancer tissues by SWATH mass spectrometry discovers N-acylethanolamine acid amidase and protein tyrosine kinase 7 as signatures for tumor aggressiveness. Mol Cell Proteomics 13:1753-68
Sun, Shisheng; Zhou, Jian-Ying; Yang, Weiming et al. (2014) Inhibition of protein carbamylation in urea solution using ammonium-containing buffers. Anal Biochem 446:76-81

Showing the most recent 10 out of 40 publications