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Cardio Program of Excellence in Glycosciences














Natasha E. Zachara Ph.D.

Assistant Professor

Address:
WBSB 408
Department of Biological Chemistry
The Johns Hopkins University School of Medicine
725 N. Wolfe Street
Baltimore, MD 21205-2185, USA

Contact:

Office Phone: 410-955-7049
Lab Phone: 410-502-3210
Fax: 410-955-5759
Website: Zachara Lab Website





One goal of this project is to determine the role of O-GlcNAc in regulating the cardioprotective process of autophagy. Pictured here, RFP-LC3 positive autophagosomes.



Highlighting the importance of O-GlcNAc, deletion of the O-GlcNAc transferase is lethal in embryonic fribroblasts. Pictured here, cells 96h after the deletion of the O-GlcNAc transferase.

IMG_1171.JPG



The Zachara Lab (March 2016). Roger Henry, Michael McCartin, Marissa Martinez, Ph.D., Kamau Fahie Ph.D., Jennifer Groves, Chloe Ferris and Gokben Yildirir.

Project 2

O-GlcNAc and Cardioprotection

Recently, the modification of nuclear, mitochondrial, and cytoplasmic proteins by O-linked beta-N-acetylglucosamine (O-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 O-GlcNAc in both in vivo and in vitro models. Elevating O-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 O-GlcNAc is a novel endogenous cardioprotective agent. Moreover, studies in animals suggest that drug-induced elevation of O-GlcNAc, immediately after a heart-attack substantially reduces tissue damage.

The molecular mechanisms by which O-GlcNAc regulates protein function leading to enhanced cell survival and cardioprotection have not been identified, which precludes the development of novel O-GlcNAc-based therapeutics. In collaboration with the other projects and cores, we will identify proteins that are O-GlcNAc modified in response to ischemic preconditioning and how this is altered by pharmacological agents that promote cardioprotection. 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.


Highlights

Recent Publications

Tapar

ra K., Tran P., and Zachara N.E. (2016) Hijacking the Hexosamine Biosynthetic Pathway to Promote EMT-Mediated Neoplastic Phenotypes. Frontiers in Oncology, 6:85.

Fa

hie, K, and Zachara N.  Molecular Functions of Glycoconjugates in Autophagy, Journal of Molecular Biology, In Press.

Lee A., Henry R., Miller D., Paruchuri V.D.P., O’Meally R., Boronina T., Cole R.N., Zachara N.E. Combined Antibodu/Lectin Enrichment Identified Extensive Changes in the O-GlcNAc Sub-Proteome. In revision.

Hou C.W., Mohanan V., Zachara N.E., Grimes C.L. (2015) Identification and biological consequences of the O-GlcNAc modification of the human innate immune receptor, Nod2. Glycobiology, 26(1):13-8. doi: 10.1093/glycob/cwv076.

Zhu Y, Liu TW, Madden Z, Yuzwa SA, Murray K, Cecioni S, Zachara N, Vocadlo DJ. (2015) Post-translational O-GlcNAcylation is essential for nuclear pore integrity and maintenance of the pore selectivity filter. J Mol Cell Biol., , 8(1):2-16. doi: 10.1093/jmcb/mjv033.

Reeves R., Lee A., Henry R., and Zachara N.E. Characterization of the Specificity of O-GlcNAc Reactive Antibodies Under Conditions of Starvation and Stress. Accepted at Analytical Biochemistry, accepted. 2014: 457: 8-18.

Tardio L*, Andrés-Bergós J*, Zachara NE, Larrañaga-Vera A, Rodriguez-Villar C, Herrero-Beaumont G, Largo R. O-linked N-Acetylglucosamine (O-GlcNAc) protein modification is increased in the cartilage of patients with knee osteoarthritis. Osteoarthritis Cartilage. 22(2):259-63. * Denotes co-first authors

Groves J., Lee A., Yildirir G., and Zachara N.E. (2013) Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis. Cell Stress and Chaperones, Sep;18(5):535-58.

Jensen R.V., Zachara N.E., Nielsen P.H., Kimose H.H., Kristiansen S.B., and Botker H.E. (2013) Impact of O-GlcNAc on cardioprotection by remote ischemic preconditioning in non-diabetic and diabetic patients.  Cardiovascular Research, 97(2): 369-378. 

Jensesn R.V., Johnsen J., Kristiansen S.B., Zachara N.E. and Botker H.E. (2013) Bschemic Preconditioning Increases Myocardial O-GlcNAc Glycosylation. Scandinavian Cardiovascular Journal, 47(3):168-74

News

Congratulations to Jennifer Groves who won a poster award at the VIIth International Symposium on Heat Shock Proteins in Biology and Medicine.

Congratulations to Marissa Martinez whose paper has been accepted in Proteomics.

Congratulations to Jennifer Groves who was awarded an NRSA by the National Institute of Aging.

Congratulation to Marissa Martinez Ph.D. who won a poster award at InterPEG.

Congratulations to Jennifer Groves who won a travel award to attend the ASBMB annual meeting.

Congratulations to Kamau Fahie Ph.D., who won a travel award to attend the Society for Glycobiology Meeting.

Congratulations to Kamau Fahie Ph.D., who was awarded an AHA post-doctoral fellowship.

Congratulations to Albert Lee Ph.D., who won a travel award to attend the Society for Glycobiology Meeting.


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