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Drug Discovery Research

Beranova-Giorgianni

Biography/Description

Sarka Beranova-Giorgianni, Ph.D.
Associate Professor
Department of Pharmaceutical Sciences
881 Madison Avenue, Room 445
Memphis, TN 38163
Phone: 901-448-5433
Email: sberanova@uthsc.edu 

Education:

  • D., University of Akron, Akron, Ohio, Analytical chemistry
  • S., Prague Institute of Chemical Technology, Prague, Czechoslovakia, Organic chemistry

Research Specialty:

Bioanalytical chemistry; biological mass spectrometry; qualitative and quantitative proteomics; targeted protein and phosphoprotein identification/characterization.

Research Interests:

My long-term research interests focus on the application of high-end biological mass spectrometry and bioinformatics technologies for qualitative and quantitative characterization of complex biological systems in health and disease. My laboratory houses a cutting-edge high-resolution LC-MS/MS instrument (Waters Synapt G2-Si) and advanced bioinformatics tools, including the Progenesis QIP software. Our team is currently applying targeted and global-scale strategies to examination of the effects of oxidative stress on the molecular machinery in retinal pigment epithelium (RPE) in vitro and in vivo. The main goal of this research is to bring new mechanistic insights into RPE dysfunction in age-related macular degeneration (AMD), and to identify new targets to be exploited for development of therapeutic interventions to halt disease progression. In the bioanalytical area, we focus on development of new and improved workflows for deep quantitative proteome profiling, proximity proteomics, and phosphoproteomics.

 

Members and Collaborators

Laboratory Members:

Sarka Beranova-Giorgianni, PhD (PI)
Diwa Koirala, Graduate student 

Collaborators:

Francesco Giorgianni, Ph.D. UTHSC COP Department of Pharmaceutical Sciences
Marko Radic, Ph.D. UTHSC COM Department of Microbiology, Immunology and Biochemistry
R.K. Rao, Ph.D. UTHSC COM Department of Physiology 

Projects

Within the general theme of oxidative stress and RPE dysfunction, we focus on investigation of the mechanistic roles of scavenger receptors in mediating the effects of oxidized lipoproteins (oxLDL) on the retinal pigment epithelium (RPE).  We are currently pursuing two directions: (1) We are testing the hypothesis that response of RPE to oxidized lipoproteins includes production of extracellular vesicles (EVs) carrying molecular cargo (mRNA and proteins), which affects response of proximal RPE to oxidative stress. We are using global-scale bioanalytical strategies to characterize the molecular constituents in the EVs and pinpoint components responsible for EV-mediated effects on proximal cells.  (2) We are investigating the retinal proteomes in mouse models of AMD to identify protein networks associated with age-related progression of oxidative stress-induced tissue damage.

Selected Publications
  1. Iannaccone, A.; Hollingsworth, T.J.; Koirala, D.; New, D.D.; Lenchik, N.; Beranova-Giorgianni, S.; Gerling, I.C.; Radic, M.Z.; Giorgianni, F. Retinal pigment epithelium and microglia express the CD5 antigen-like protein, a novel autoantigen in age-related macular degeneration. Exp. Eye. Res. 155, 64-74, 2017.
  2. Giorgianni F, Beranova-Giorgianni S. Phosphoproteome Discovery in Human Biological Fluids. Proteomes 4, 37, 2016.
  3. Iannaccone, A.; Giorgianni, F.; New, D.D.; Hollingsworth, T.J.; Umfress, A.; Alhatem, A.H.; Neeli, I.; Lenchik, N.I.; Jennings, B.J.; Calzada, J.I.; Satterfield, S.; Mathews, D.; Diaz, R.I.; Harris, T.; Johnson, K.C.; Charles, S.; Kritchevsky, S.B., Gerling, I.C.; Beranova-Giorgianni, S.; Radic, M.Z. Circulating autoantibodies in age-related macular degeneration recognize human macular tissue antigens implicated in autophagy, immunomodulation, and protection from oxidative stress and apoptosis. PLOS ONE 10, e0145323, 2015. 
  4. Dong Q, Giorgianni F, Beranova-Giorgianni S, Deng X, O'Meally RN, Bridges D, Park EA, Cole RN, Elam MB, Raghow R. Glycogen synthase kinase-3-mediated phosphorylation of serine 73 targets sterol response element binding protein-1c (SREBP-1c) for proteasomal degradation. Biosci Rep. 36, e00284, 2015.
  5. Giorgianni, F.; Koirala, D.; Weber, K.T.; Beranova-Giorgianni, S. Proteome analysis of subsarcolemmal cardiomyocyte mitochondria: a comparison of different analytical platforms. Int. J. Mol. Sci. 15, 9285-9301, 2014.

 

Hevener

Description

The Hevener laboratory focuses on preclinical infectious diseases drug discovery, antimicrobial target validation and characterization, and structural mechanisms of bacterial resistance. Current research areas include enzyme targets in the bacterial fatty acid synthesis pathway (FAS-II) and bacterial type 1a topoisomerases. Areas of laboratory expertise include structure- and ligand-based drug discovery, computer-aided drug discovery, protein biochemistry, and structural biology.

Dr. Kirk Hevener is an academic pharmacist and pharmaceutical scientist with research expertise in medicinal chemistry, computational chemistry, protein biochemistry, and structural biology.  Dr. Hevener earned a Bachelor of Science degree in Physical Organic Chemistry from Tennessee State University followed by a PharmD and PhD from the University of Tennessee Health Science Center.  Dr. Hevener completed postdoctoral fellowships at St. Jude Children's Research Hospital and the University of Illinois at Chicago, supported during the latter as an NIH NRSA Fellow.  Dr. Hevener was a junior faculty member at Idaho State University’s College of Pharmacy in Meridian, ID from 2013 to 2017 and has joined the faculty at University of Tennessee, College of Pharmacy in March, 2017.

Contact Information:
881 Madison Ave. Ste 571
Memphis, TN 38163
khevener@uthsc.edu
Office – 901-448-1474
https://www.facebook.com/HevenerLaboratory
https://twitter.com/HevenerLab

Members and Collaborators

Lab Personnel
Dr. Adrianna Barba-Montoya, Postdoctoral Research Fellow, Protein Biochemistry
Dr. Jesse A. Jones, Graduate Research Assistant, Structural Biology & Protein Biochemistry
Dipesh Budhathoki, Lab Alumnus, Computational Chemistry

Collaborators
Dr. Julian Hurdle, Texas A&M Health Science Center, Microbiology & Bacteriology (FabK Project)
Dr. Dianqing Sun, University of Hawaii at Hilo, Synthetic Medicinal Chemistry (FabK Project)
Dr. Ying Kong, UTHSC Dept. of Microbiology, Immunology, & Biochemistry (Topoisomerase Project)
Dr. Jiawang Liu, UTHSC Medicinal Chemistry Core, Synthetic Chemistry (Topoisomerase Project)

Projects
  1. Investigation of the FAS-II enzyme, FabK, as a narrow-spectrum, druggable target for C. difficile
    Drug-resistant C. difficile infection poses a serious threat to public health and contributes to over 29,000 deaths in the U.S. per year. This research proposes to investigate a key enzyme in the bacterial fatty acid synthesis pathway, enoyl-ACP reductase II (FabK), as a novel, druggable target for selective therapy of C. difficile infection (CDI). 
  1. Investigation of Streptococcal Topoisomerase I as a Narrow-Spectrum Antibacterial Target
    Streptococcal infections are amongst the most common bacterial infections in humans, and contribute to a staggering economic burden for their treatment. Alarming trends of increasing antibacterial resistance among these organisms demonstrate the importance of identifying newer treatment approaches. This research proposes to investigate an essential bacterial enzyme in Streptococcal topoisomerase I, as a potentially selective target for the prevention and treatment of streptococcal-associated infection.
Selected Publications
  1. Recent Advances in the Rational Design and Optimization of Antibacterial Agents.  JA Jones, KG Virga, G Gumina, KE Hevener* MedChemComm. 2016, 7 (9), 1694-1715.  MedChemComm ‘Hot Article’
  2. Rifamycin Resistance in Clostridium difficile is Generally Associated with a Low Fitness.  Dang U, Zamora I, Hevener KE, Adhikari S, Wu X, Hurdle JG. Antimicrob Agents Chemother. 2016, 60 (9), 5604-5607.
  3. A simplified protocol for high-yield expression and purification of bacterial topoisomerase I. Jones JA, Price E, Miller D, Hevener KE*. Protein Expr Purif. 2016, 124, 32-40.
  4. Comparison of radii sets, entropy, QM methods, and sampling on MM‐PBSA, MM‐GBSA, and QM/MM‐GBSA ligand binding energies of F. tularensis enoyl‐ACP reductase (FabI).  Su PC, Tsai CC, Mehboob S, Hevener KE*, Johnson ME*. J Comp Chem. 2015, 36 (25), 1859-1873.
  5. Structural and Biological Evaluation of a Novel Series of Benzimidazole Inhibitors of Francisella tularensis Enoyl-ACP Reductase (FabI).  Mehboob S, Song J, Hevener KE, Su PC, Boci T, Brubaker L, Truong L, Deng J, Cook JL, Santarsiero BD, Ghosh AK, Johnson ME.Bioorg Med Chem Lett.2015, 25 (6), 1292-1296.
  6. High-throughput screening (HTS) and hit validation to identify small molecule inhibitors with activity against NS3/4A proteases from multiple Hepatitis C Virus genotypes.  Lee H, Zhu T, Patel K, Zhang YY, Truong L, Hevener KE, Subramanya G, Gatuz JL, Sarkar A, Jeong HY, Uprichard SL, and Johnson ME. PLoS One.2013, 8 (10), e75144.
  7. Hit Identification and Optimization in Virtual Screening: Practical Recommendations Based Upon a Critical Literature Analysis.  Tian Zhu, Shuyi Cao, Pin-Chih Su, Ram Patel, Darshan Shah, Heta B. Chokshi, Richard Szukala, Michael E. Johnson, Kirk E. Hevener*J Med Chem. 2013, 56 (17), 6560-6572.
  8. Synergistic Inhibitor Binding to the Papain-Like Protease of Human SARS Coronavirus: Mechanistic and Inhibitor Design Implications.  Lee H, Cao S, Hevener KE, Truong L, Gatuz JL, Patel K, Ghosh AK, and Johnson ME. ChemMedChem. 2013, 8 (8), 1361-1372.
  9. Fragment-based lead discovery using a multi-domain, parallel MM/PBSA simulation screening protocol.  Zhu T, Lee H, Lei H, Jones C, Patel K, Johnson ME, Hevener KE*.  J Chem Inf Model.2013, 53 (3), 560-572.
  10. High-level expression, purification, and characterization of Staphylococcus aureus dihydrootase (PyrC) as a cleavable His-SUMO fusion.  Truong L, Hevener KE, Rice AJ, Patel K, Johnson ME, Lee H. Protein Expr Purif. 2013, 88 (1), 98-106.

 

Yates

Description
Dr. Yates’ research interest is in drug discovery and development of small molecules that modulate pro-inflammatory signaling cascades associated with aberrant cellular proliferation and migration.
Members and Collaborators
Ling Lin, MS (graduate student)
Projects
Growth factors, e.g., VEGF and IGF-1, are implicated in pathologic ocular neovascularization. Consequently, anti-VEGF delivered via intravitreal injection represents one of the most widely utilized approaches to treat age-related macular degeneration and diabetic macular edema. Concerns over chronic anti-VEGF treatment exist, however, due to the fact that VEGF is required for survival of endothelial cells of the choriocapillaries. Development of next generation therapeutics requires, not only identification of novel targets and associated signaling cascades, but also topical formulations for delivery of drug to the back of the eye. Our laboratory has discovered two platforms for modulating angiogenesis in the eye. The first is based on a chemical probe that disrupts the Src/FAK/paxillin signalsome upon VEGF stimulation. The second acts as a biased agonist of the IGF-1 receptor, which promotes cell survival by selectively activating the Akt signaling pathway. We have developed an ocular microemulsion drug delivery system, which has been used to demonstrate that topical application of either platform results in suppression of pathologic retinal neovascularization in the murine oxygen-induced retinopathy model. Current research is focused on elucidation of the structural biology of target/probe interactions using supercomputing, optimization of the ocular microemulsion to improve back of the eye delivery, and further characterization of the anti-angiogenic mechanisms of each platform.
Selected Publications
  1. Zhousheng Xiao, Jerome Baudry, Li Cao, Jinsong Huang, Charles R. Yates, Jeremy C. Smith, L. Darryl Quarles. Polycystin-1 interacts with TAZ to stimulate osteoblastogenesis and inhibit adipogenesis. Journal of Clinical Investigation (in press).
  2. Christian Bime, Nima Pouladi1,, Saad Sammani, Ken Batai, Nancy Casanova, Tong Zhou, Carrie L. Kempf, Xiaoguang Sun, Sara M. Camp, Ting Wang, Rick A. Kittles, Yves A. Lussier, Tiffanie K. Jones, John P. Reilly, Nuala J. Meyer, Jason D. Christie, Jason Karnes, Manuel Gonzalez-Garay, David C. Christiani, Charles R. Yates, Mark M. Wurfel, Umberto Meduri , Joe G. N. Garci. GWAS in African Americans identifies the Selectin P Ligand gene, SELPLG, as an ARDS risk gene. AJRCCM Blue Journal (in press).
  3. Velazquez, HA, Riccardi, D, Xiao, Z, Quarles, LD, Yates, CR, Baudry, J, Smith, JC. Ensemble Docking to Difficult Targets in Early-Stage Drug Discovery: Methodology and Application to Fibroblast Growth Factor 23. Chem Biol Drug Des, 2017.
  4. He, H, Ma, D, Crone, LB, Butawan, M, Meibohm, B, Bloomer, RJ, Yates, CR. Assessment of the Drug-Drug Interaction Potential Between Theacrine and Caffeine in Humans. J Caffeine Res, 7 (3), 95-102, 2017.
  5. He, H, Weir, RL, Toutounchian, JJ, Pagadala, J, Steinle, JJ, Baudry, J, Miller, DD, Yates, CR. The quinic acid derivative KZ-41 prevents glucose-induced caspase-3 activation in retinal endothelial cells through an IGF-1 receptor dependent mechanism. PLoS One, 12 (8), e0180808, 2017.
  6. Toutounchian, JJ, Pagadala, J, Miller, DD, Baudry, J, Park, F, Chaum, E, Yates, CR. Novel Small Molecule JP-153 Targets the Src-FAK-Paxillin Signaling Complex to Inhibit VEGF-Induced Retinal Angiogenesis. Mol Pharmacol, 91 (1), 1-13, 2017.
  7. Richard J. Bloomer, and Charles R. Yates. Dietary supplement usage: Better science equals better outcomes. Journal of Food and Nutrition, 2 (3), 27, 2017.
  8. Xiao, Z, Riccardi, D, Velazquez, HA, Chin, AL, Yates, CR, Carrick, JD, Smith, JC, Baudry, J, Quarles, LD. A computationally identified compound antagonizes excess FGF-23 signaling in renal tubules and a mouse model of hypophosphatemia. Sci Signal, 9 (455), ra113, 2016.
  9. Deng, W, Kimura, Y, Gududuru, V, Wu, W, Balogh, A, Szabo, E, Thompson, KE, Yates, CR, Balazs, L, Johnson, LR, Miller, DD, Strobos, J, McCool, WS, Tigyi, GJ. Mitigation of the Hematopoietic and Gastrointestinal Acute Radiation Syndrome by Octadecenyl Thiophosphate, a Small Molecule Mimic of Lysophosphatidic Acid. Radiat Res, 2015.
  10. Umberger, R, Thompson, CL, Cashion, AK, Kuhl, D, Wan, J, Yates, CR, Muthiah, MP, Meduri, GU. Exaggerated plasma Interleukin 6, Interleukin 10, and Subsequent Development of Health Care-Associated Infections in Patients With Sepsis. Dimens Crit Care Nurs, 34 (2), 100-11, 2015.
  11. Patil, R, Szabó, E, Fells, JI, Balogh, A, Lim, KG, Fujiwara, Y, Norman, DD, Lee, SC, Balazs, L, Thomas, F, Patil, S, Emmons-Thompson, K, Boler, A, Strobos, J, McCool, SW, Yates, CR, Stabenow, J, Byrne, GI, Miller, DD, Tigyi, GJ. Combined Mitigation of the Gastrointestinal and Hematopoietic Acute Radiation Syndromes by an LPA2 Receptor-Specific Nonlipid Agonist. Chem Biol, 2015.
  12. Toutounchian, JJ, Steinle, JJ, Makena, PS, Waters, CM, Wilson, MW, Haik, BG, Miller, DD, Yates, CR. Modulation of Radiation Injury Response in Retinal Endothelial Cells by Quinic Acid Derivative KZ-41 Involves p38 MAPK. PLoS One, 9 (6), e100210, 2014.

Last Published: Nov 7, 2017