Research

Principal investigator:
Michael McVoy

Lab members:
Jian Ben Wang, Xiaohong Cui, Anne Sauer, Ronzo Lee, Sabrina Prescott, Sukhada Bhave, Jeff Donowitz, Brent Stanfield

Lab contact:
Michael McVoy
Location: 12-026 Sanger Hall
Phone: (804) 828-2991

Current projects:

• Preclinical development of human CMV vaccines (National Institute of Allergy and Infectious Diseases/NIH/DHHS)
• Viral immunomodulation and rational CMV vaccine design (University of Minnesota)

Research interests:
The mission of our laboratory is to improve human health by developing new tools to combat a very serious pathogen, human cytomegalovirus (HCMV). We are approaching this problem through two avenues: understanding the basic mechanisms of herpes virus genome replication and maturation, with an aim toward development of novel antiviral drugs; and exploring novel approaches to vaccine design.  

Herpesvirus DNA maturation 
Terminase. Herpesviruses replicate their DNA in the form of concatemers — long DNA molecules comprised of many viral genomes linked together in a “daisy chain” like structure. The genome on the end is “packaged” into a preformed capsid, but must then be liberated from the concatemer by a precise cut of the DNA. Both the packaging and the cleavage of the DNA are mediated by an enzymatic complex called terminase. Because normal cells do not package or cleave DNA, this process is an attractive target for development of new antivirals. In collaboration with Deborah Parris at Ohio State University, we are currently focused on expression and purification of terminase subunits and their biochemical evaluation in vitro. 

Alkaline nuclease. While genetic studies suggest this protein is critically important for HCMV replication, its function remains a mystery. Through in silico modeling, mutagenesis and recombinant protein expression, we have identified critical amino acids required for enzymatic activity. Current efforts are focused on insertion of these mutations into the viral genome to evaluate their impact on viral replication and in silico compound library screening to identify candidate inhibitors.

Novel approaches to HCMV vaccines
The guinea pig cytomegalovirus (GPCMV) vaccine model. GPCMV is the only small animal CMV that causes fetal infection and pathogenesis. In collaboration with Mark Schleiss and Alistair McGregor at the University of Minnesota, we have worked to develop molecular and immunological tools to expand the utility of this model. The complete genome has been sequenced and a number of potential immune evasion genes identified. In particular, three genes encoding MHC class I homologs appear to be NK evasins. An infectious BAC clone was also constructed. Current projects will define the role of MHC I homologs and their potential to augment live or disabled vaccines. 

Antibodies that neutralize epithelial entry. The ability to elicit potent neutralizing antibody responses may be critical for a successful HCMV vaccine. We recently showed that two experimental vaccines, the Towne live attenuated vaccine and the subunit gB/MF59 vaccine, perform poorly, compared to natural infection, with respect to inducing neutralizing antibodies that block epithelial cell entry. Evidence suggests that epitopes crucial for inducing such activity lie within the gH/gL/UL128-131 complex. Current studies are focused on characterizing humoral responses to this complex and identifying vaccine strategies to induce them. Strategies of interest include DNA vaccines, subunit proteins, peptides, and live attenuated, disabled or inactivated whole virus-based approaches.

Recent publications:
Schleiss, M. R. and M. A. McVoy.  2010.  Guinea Pig Cytomegalovirus: A Model for the Study of the Prevention and Treatment of Maternal-Fetal Transmission.  Future Virology, 5:207-17. 

Sauer, A., J. B. Wang, G. Hahn., and M. A. McVoy. 2010. A Human Cytomegalovirus Deleted of Internal Repeats Replicates with Near Wild Type Efficiency but Fails to Undergo Genome Isomerization.  Virology, 401:90-5.

View more

Principal investigator:
Paul H. Ratz, Ph.D.

Lab members:
Amy S. Miner (laboratory manager)
Michael Byrne, M.D. (urology resident)

Lab contact:
Amy Miner
Location: Sanger Hall, rooms 12-031, 12-029, 12-027
Phone: (804) 828-6812

Research interests:
The focus of my laboratory is regulation of smooth muscle contraction, specifically vascular and urinary bladder. We currently have joined forces with Department of Emergency Medicine (VCURES) to work on a project to understand the subcellular mechanisms causing vascular hyporeactivity during hemorrhagic, septic and cardiac shock. We also are working with collaborators in the Department of Surgery (Urology) to understand the mechanisms responsible for enhanced rhythmic contractile activity during the bladder filling phase that correlates with overactive bladder syndrome.

Recent publications:
Rho-kinase inhibition attenuates calcium-induced contraction in β-escin but not Triton X-100 permeabilized rabbit femoral artery. Clelland LJ, Browne BM, Alvarez SM, Miner AS, Ratz PH. J Muscle Res Cell Motil. 2011 32(2):77-88. PMID: 21706258

Prostaglandin E₂ mediates spontaneous rhythmic contraction in rabbit detrusor muscle. Klausner AP, Johnson CM, Stike AB, Speich JE, Sabarwal V, Miner AS, Cleary M, Koo HP, Ratz PH. Can J Urol. 2011 Apr;18(2):5608-14. PMID: 21504648

View more

Principal investigator:
Henry J. Rozycki, M.D.

Lab members:
Adam Brock, lab technician
Melissa Yopp, lab manager

Lab contact:
Melissa Yopp
Location: Hermes A. Kontos Medical Sciences Building, 1217 E. Marshall St.
Phone: (804) 628-2793

Current projects:
TLR4 Function And Prematurity In Type II Alveolar Epithelial Cells

Research interests:
Premature babies are at risk for developing chronic lung disease, known as BPD or bronchopulmonary dysplasia. The primary risk factor is prematurity, as well as exposure to mechanical ventilation, oxygen and infection. These factors precipitate a strong inflammatory response and, eventually lung development simplification. Our lab is investigating the inflammatory phase of BPD.

Specifically, we are investigating the role of alarmins, or danger signals produced by stressed or damaged lung cells or extracellular matrix, on TLR4 mediated inflammation, and the role of prematurity in this process. We expose lung epithelial Type II cells to different alarmins and measure the activation of inflammatory-associated transcription factors and the transcription and expression of chemokines. By blocking the response with anti-TLR4 antibodies or reducing TLR4 expression via siRNA we are determining the specificity of the response. Currently, this work is being done with the alarmins HMGB1 and low-molecular weight hyaluronic acid using the mouse MLE-12 cell line. In the next phase we will use Type II cells from fetal, newborn and adult mice and replicate the alarmin exposures to investigate the role of prematurity.

Clinically, there are current studies investigating the relationship between tracheal aspirate HMGB1 and low molecular-weight hyaluronic acid and pulmonary outcome in ELBW infants.

We are planning to compare the TLR4-specific factors produced by hyperoxia-exposed premature vs. newborn lungs in explant culture on inflammation, and to determine the role of alarmin excitation of TLR4 receptors on lung development signals such as FGF10 and BMP4.

Recent publications:
Lim L, Rozycki HJ. Postnatal SNAP-II Scores in NICU Patients: Relationship to Sepsis, Necrotizing Enterocolitis and Death. J  Maternal-Fetal Neonatal Med 2008; 19: 43-48

Altirkawi K, Rozycki HJ. Hypocalcemia Is a Common Occurrence in the First 48 Hours of Life in ELBW Infants. J Perinatal Med 2008; 36: 348-53.

View more

Principal investigator:
Bruce K. Rubin, M.Engr., M.D., M.B.A., FRCPC

Lab members:
Melissa Yopp, lab manager
Tsuyoshi Tanabe, Ph.D., senior scientists
Taduaske Shimokawaji, postdoctoral fellow
Tokita Erica, postdoctoral fellow
Chris Corday, UWE student
Shauna Webb-Parker, graduate student
Agathe Hoffer-Schaefer, part-time lab technician
Adam Brock, part-time lab technician

Lab contact:
Melissa Yopp
Locations: Hermes A. Kontos Medical Sciences Building, 1217 E. Marshall St., Room 215; and Sanger Hall, 1101 E. Marshall St., Room 8-046
Phone:(804) 628-2793

Current projects:

• Master Research Agreement (Reckitt Benckiser, Inc.)
• Testing novel drugs as potential immunomodulatory medications (Gilead Sciences, Inc.)
• The evaluation of novel macrolides as potential immunomodulatory medications for treating airway inflammation (GlaxoSmithKline)
• A single center, parallel, double-blind, placebo-controlled trial to assess the effects of Mucinex (1200 mg GGE) on mucociliary and cough clearance (MCC/CC) during an acute respiratory infection (Reckitt Benckiser, Inc.)
• Mucinex 1200 mg bid for the treatment of symptoms of an upper respiratory tract infection when two 600 mg tablets are given twice daily for 7 days (Reckitt Benckiser, Inc.)

Research interests:
There are three major themes in our research:

1. Airway inflammation. We study relationships among inflammatory cells and mediators, infection, mucus secretion, and quality of life; and the mechanisms causing squamous metaplasia and goblet cell hyperplasia. We develop and test new therapies from cell and tissue culture, to animal studies, to clinical trials.
2. Secretory hyperesponsiveness. Excessive mucus secretion is characteristic of diseases like asthma, COPD, cystic fibrosis, middle lobe syndrome and plastic bronchitis. We study the mechanisms of secretory hyperesponsiveness, characterize the biophysical and transport properties of mucus, and evaluate new therapies with collaborators from around the world. We maintain the International Registry for Plastic Bronchitis.
3. Nasal and sinus disease. We have studied the physical and transport properties of mucus and sputum for three decades. We have formed a sino-nasal research group with investigators from the Rubin lab and the departments of Ear, Nose and Throat, Allergy, Radiology, Nursing, Emergency Medicine and the School of Engineering to develop new ways to measure the impact of sinus disease and test new therapies including novel aerosol delivery systems. In our first 18 months as a group, we have been awarded three investigator-initiated research grants to study sinus disease.

Recent publications:
Rubin BK and Fink JB. Drug delivery devices and propellants in Allergy Frontiers, Therapy and Prevention. Vol 5. Springer, Tokyo. 2010 pp. 245-58.

Priftis KN and Rubin BK. Atelectasis, middle lobe syndrome, plastic bronchitis. in Pediatric Bronchoscopy Eds. K.N. Prifits, M.B. Anthracopoulos, E. Eber, A. A. Koumbourlis, R. E. Wood. Part of the Progress in Respiratory Research Series. Karger, Basil. 2011, Vol 38. pp 149-155.

View more

Principal investigator:
Wei Zhao, M.D., Ph.D.

Lab members:
Include research staff, graduate students, postdoctoral researchers

Lab contact:
Location: Mcguire Hall, 1112 E. Clay St.
Phone: (804) 828-0979

Current projects:
Co-investigator and member of Asthma and Allergic Diseases Cooperative Research Center of VCU (NIH research project; PI: Dr. Lawrence Schwartz)

Research interests:
Dr. Wei Zhao’s research interest is regulation of human mast cell function.

Our major contributions include: 1) the determination that proteases produced by human skin mast cells degrade endogenous as well as recombinant cytokines; 2) human skin derived mast cells express functional FcγRIIa, but not FcγRIIb (our data challenge the current dogma that immunotherapy works through the induction of IgG antibody, which binds to FcγRIIb and transduces inhibitory signals to cells upon allergen exposure); 3) TGF-β regulates mast cell function through inhibiting its de novo expression of kit.

Currently, we are studying the mechanism of desensitization by using both in vitro and in vivo models. Our in vitro model uses human skin derived mast cells which are sensitized to NP-IgE and then desensitized with NP-BSA. On the other hand, penicillin allergic patients are recruited to undergo desensitization. In addition to monitoring their hypersensitivity status before and after desensitization, basophils are isolated and tested ex vivo for their ability to respond to different stimuli. This research project will help to answer critical questions such as the duration of desensitization, the status of cross-desensitization, and the underlying cellular and molecular mechanism of drug desensitization.

Recent publications:
Gomez G, Zhao W, Schwartz LB. Disparity in FcεRI-induced degranulation of primary human lung and skin mast cells exposed to adenosine.J Clin Immunol. 2011 Jun;31(3):479-87. Epub 2011 Mar 25.