Research

Principal investigator:
Michael McVoy

Lab members:
Jian Ben Wang
Xiaohong Cui
Anne Sauer
Ronzo Lee Sabrina Prescott Ying Qi
Zainab Al-Mahdi
Zohaib Alam

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 herpesvirus 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 ofterminase 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. In 2008, we 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:

Saccoccio, F. M., M. K. Gallagher, S. P. Adler, and M. A. McVoy. 2011. Neutralizing Activity of Saliva against Cytomegalovirus. Clinical and Vaccine Immunology, 18:1536-1542. PMC3165217  Free PMC Article

Kuchta, A. L., H. Parikh, Y. Zhu, G. E. Kellogg, D. S. Parris, and M. A. McVoy. 2012. Structural modelling and mutagenesis of human cytomegalovirus alkaline nuclease UL98. The Journal of General Virology 93:130-138. PMC3352332  Free PMC Article

Cui, X., S. P. Adler, A. J. Davison, L. Smith, S. E. Habib el, and M. A. McVoy. 2012. Bacterial artificial chromosome clones of viruses comprising the towne cytomegalovirus vaccine. J Biomed Biotechnol 2012:428498. PMC3236503  Free PMC Article

Wang, J. B., Y. Zhu, M. A. McVoy, and D. S. Parris. 2013. Changes in subcellular localization reveal interactions between human cytomegalovirus terminase subunits.  Virology Journal, 9:315. PMID: 23259714  Free full text

Yang, D., K. Tamburro, D. Dittmer, X. Cui, M. McVoy, N. Hernandez, and M. Schleiss.  2013.  Complete Genome Sequence of Pathogenic Guinea Pig Cytomegalovirus from Salivary Gland Homogenate of Infected Animals.  Genome Announcements, 1:1. PMID: 23516193  Free PMC Article

Cui, X., R. Lee, S. P. Adler, and M. A. McVoy. 2013. Antibody inhibition of human cytomegalovirus spread in epithelial cell cultures. J Virol Meth, 192:44-50 PMID: 23669101

Bhave, S., H. Elford, and M. A. McVoy. 2013. Ribonucleotide reductase inhibitors hydroxyurea, didox, and trimidox inhibit human cytomegalovirus replication in vitro and synergize with ganciclovir.  Antiviral Research, in press.

Principal investigator:
Karen D. Hendricks-Muñoz

Lab members:
Jie Xu, Ph.D. (research scientist and lab manager)
Joseph El Khoury M.D. (assistant professor)
Tazuddin Mohammed (assistant professor)
Jenny Fox, M.D. (neonatal fellow research)

Research interests:

Scientific investigations aim to understand:

• The role of the developing and developed microbiome on infant short and long term nutrition, immunity and overall health
• The role of stress on mucosal oral components (regulatory hormones cortisol, leptin, EGF, cytokines and mucins) selection of early oral and gut microbial signature patterns
• Microbial and cytokine patterns of healthy oral and gut function in the developing infant to use as markers of risk of disease, such as NEC or chronic lung disease
• The role of parental touch as an infant pain modifier, microbial selector and innate immune stimulator especially the use of Kangaroo Mother Care (KMC)
• The identity of bacterial signatures important for development of a healthy microbiome with attention to oral, pulmonary and gut mucosal bacterial anchorage and bacterial selection modifiers in the naïve host
• The barriers to microbiome acquisition and colonization patterns that impact on enhanced nutritional /innate immune function
• The importance of temporal environmental exposures, such as pollutants, the NICU environment and host selection of first microbes important as health protectors against subsequent pathogens and later health challenges
• The link between microbial selection and inflammatory endothelial dysfunction associated with diseases such as ROP, NEC and IVH in the high risk preterm infant, metabolic (diabetes/obesity) and inflammatory disorders (asthma, cardiovascular diseases-coronary/HTN and congenital muscular dystrophies where inflammation linked endothelial dysfunction play important roles
• The role of microbiome drug relationships (antibiotics, steroids, statins and others) as modulators of drug health effects
• Other specific interests include: ventilator and nutritional strategies to improve respiratory outcome, clinical quality excellence through evidence based medicine and clinical care plans and the role and methods to motivate provider perceptions on care expectations to improve parental-infant interaction and neurodevelopmental outcome

Recent publications:

Kasat K, Hendricks-Muñoz KD, Mally P Neonatal Red Blood Cell Transfusions:  Searching for Better Guidelines, Blood Transfusion 9: 86-94, 2011

Bailey S, Hendricks-Muñoz KD, Mally P. Animal Origins of Surfactant: Physician Perception and Practice Regarding Parent Information Sharing in Neonatal Intensive Care. Am J. Bioethics AJOB Primary Research, 2: 1, 26-33, 2011

Gordon PV, Seidner SR, Davis JM, Schelonka R, Durand DJ, Segar J, Watterberg K, Hendricks-Munoz, KD et al. Regarding Part IV of Recertification in Neonatology: A Consensus Perspective of 69 Academic Neonatology Section Heads. eJournal of Neonatology Research 1:1 eJNR21606072v1i1p7y2011

Curatola AM, Xu J, and Hendricks-Munoz KD*. Cyclic GMP Protects Endothelial Progenitors from Oxidative Stress. Angiogenesis, 14;267, 2011.

Schulman J, Stricof R, Stevens TP, Horgan M, Gase K, Holzman IR, Koppel RI, Nafday S, Gibbs K, Angert R, Simmonds A, Lisa Saiman, the NYS Regional Perinatal Centers ( Hendricks-Munoz, KD)  Statewide NICU Central-Line-Associated Bloodstream Infection Rates Decline After Bundles and Checklists. Pediatrics 127:436-444, 2011.

Bautista, A, Eng WS, Hendricks-Muñoz, KD, Mahal L. Identification of a Conserved Glycan Signature for Microvesicles. Journal of proteome research. 10: 4624 (#J0225257), 2011

Bailey S, Hendricks-Muñoz KD, Mally P. Near-infrared Spectroscopy SCORE (Splanchnic-Cerebral Oxygenation Ratio Evaluation) Can Help Determine Premature Infant Blood Transfusion Needs". Transfusion. Feb;52(2):252-60. PMID: 21790634 , 2012.

Mally P, Bailey S, Hendricks-Muñoz KD*. Incidence and Etiology of Late Preterm Admissions to the Neonatal Intensive Care Unit and Its Associated Respiratory Morbidities When Compared to Term Infants. Am J Perinatol.. 2012 Oct 24. PMID:23096053.

Hendricks-Muñoz KD*, Guillermo Perez-Perez, Xu, J, Kim Y, Louie M, Maternal Antenatal Treatments Influence initial oral bacterial acquisition in the Preterm Infant.  Am J Perinatology  Jan;30(1):47-52. PMID: 23359231 [PubMed  , 2013

Bailey SM, Hendricks-Muñoz KD, Mally P. Parental Influence on the Clinical Management during Neonatal Intensive Care: A survey of US Neonatologists. J of Maternal Fetal and Neonatal Medicine 2013 Aug;26(12):1239-44 PMID: 23414460 , 2013.

Hendricks-Muñoz KD*, Li Y, Kim Y, Louie M. Maternal and neonatal nurse perspectives on the value of Kangaroo Mother Care (KMC) and maternal-care partnership in the Neonatal Intensive Care Unit (NICU).  PMID:23359231 Am J Perinatology Jan,28 2013 ahead of print

Bailey SM, Hendricks-Muñoz KD, Mally P. Cerebro-splanchnic oxygen ratio(CSOR) values in  Healthy Term Newborn Infants as measured by near-infrared spectroscophy (NIRS)", Pediatric Surgery International PMID: 23456284 , Feb 28, 2013.

Suguna Narasimhulu S, Hendricks-Muñoz KD, Borkowsky W, Mally P. Usefulness Of Urinary Immune Biomarkers In Evaluation Of Neonatal Sepsis: A Pilot Project. Clinical Pediatrics Clin Pediatr (Phila). 2013 Jun;52(6):520-6. PMID 23539685 . Epub 2013 Mar 28

Bailey SM, Hendricks-Muñoz KD, Mally P. Cerebral, renal, and splanchnic tissue oxygenation saturation values in healthy term newborn infants. PMID: 23873114  Am J of Perinatology, 2013.

Abstracts and presentations

Mora R, Hendricks-Muñoz KD. Retinal Vascular Growth Is Delayed by Caffeine Treatment for Apnea of Prematurity. Poster Society of Pediatric Research 2011 Denver Co

Narasimhulu S,, Hendricks-Muñoz KD, Mally P. Usefulness of Urinary Biomarkers in Evaluation of Neonatal Sepsis: A Pilot  Platform Society of Pediatric Research 2011 Denver Co

Hoang T, Hendricks-Munoz KD, Kim Y.  "Impact of Multidisciplinary Team Approach on Late-Onset Infection Rate"  Poster Society of Pediatric Research 2011 Denver Co

Mally P, Caprio M, Jean P, Hendricks-Muñoz KD. "Patient-Ventilator Interaction during Conventional Ventilation and during Neurally Adjusted Ventilator Assist (NAVA) in Intubated Neonates Poster Society of Pediatric Research 2011 Denver Co

Mally P, Bailey S, Narasimhulu S, Hendricks-Muñoz KD.  "Impact of Routine Neonatal Intensive Care [NICU] Monitoring on Late Pre-Term Infants [LPT]" Poster Society of Pediatric Research 2011 Denver Co

Narasimhulu S, Hendricks-Muñoz KD, Mally P. "Urinary Cytokines as biomarker of early newborn sepsis.  Platform, Eastern Society of Pediatric Research 2011 Philadelphia.

Narasimhulu S, Hendricks-Munoz KD, Mally P. "Urinary Cytokines as biomarker of early newborn sepsis.  New York Perinatal Society, 2011.

Mora R, Hendricks-Muñoz KD. Retinal Vascular Growth Is Delayed by Caffeine Treatment for Apnea of Prematurity", New York Perinatal Society, 2011.

Narasimhulu S, Hendricks-Muñoz KD, Mally P. "Urinary Cytokines as biomarker of early newborn sepsis.  Platform, Society of Pediatric Research 2011 Denver Co, 2011

Mora R, Hendricks-Muñoz KD. Retinal Vascular Growth Is Delayed by Caffeine Treatment for Apnea of Prematurity", abstract #753473, Society of Pediatric Research, Denver Co, 2011

Mally P, Caprio M , Jean P, Hendricks-Munoz, KD: "Patient-Ventilator Interaction during Conventional Ventilation and during Neurally Adjusted Ventilator Assist (NAVA) in Intubated Neonates: Society of Pediatric Research 2011 Denver Co, 2011

Mally P, Bailey S, Narasimhulu S, Hendricks-Muñoz KD. "Impact of Routine Neonatal Intensive Care [NICU] Monitoring on Late Pre-Term Infants : Society of Pediatric Research 2011 Denver Co, 2011

Plateroti, P, Hendricks-Muñoz, KD, Xu J and Curatola AM. Effects of Caffeine on Retinal Endothelial Cells: Implications for Retinopathy of Prematurity. 37th Annual Meeting of the European Paediatric Ophthalmological Society (EPOS), June 17th, 2011 

Cruz H, Hendricks-Muñoz, KD, Wachtel E. Initial Clinical Characteristics predictive of progression of neonatal encephalopathy and need for Hypothermia Therapy. Society of Pediatric Research, June 2012

Aguirre A, Kim Y, Caprio M, Hendricks-Muñoz, KD, Impact of availability of tertiary cardiac surgical services at birth on neonatal cardiac preoperative outcome” Preoperative differences of neonates born at hospitals with and without cardiac surgical services” Society of Pediatrics Research, May 2012

Mally P, Bailey S, Hendricks-Muñoz KD. Clinical outcomes of early term infants Society of Pediatrics Research, May 2012

Bailey S, Mally P, Hendricks-Muñoz KD. Cerebral tissue oxygen saturation in the healthy term infant. Society of Pediatrics Research, May 2012

Wachtel E, Hendricks-Muñoz KD. Impact of Antenatal Placental Insufficiency on Long Term Postnatal Growth and Neurodevelopmental Outcome. Society of Pediatrics Research, May 2012

Hoang T, Hendricks-Muñoz KD, Mally P. Establishing Normograms for Salivary Cytokines as a Biomarker for Early Onset Sepsis, Society of Pediatrics Research, May 2012

Hoang T, Hendricks-Muñoz KD, Bailey S. Antenatal Magnesium therapy impact on neonatal clinical outcome. Society of Pediatrics Research, May 2012

Pennesi C, Hoang T, Kim Y, Hendricks-Muñoz KD*. Impact of Structured Kangaroo Mother Care Nursing Training on Nursing Competency and Utilization of KMC. Society of Pediatrics Research, May 2013

Karam S, Hendricks-Muñoz KD, Xu J, Rozycki H. Multiplex cytokine analysis from trancheal aspirates in ELBW infants: Relationships to ventilation and outcomes. Society of Pediatrics Research, May 2013

Russo-Menna I, Carter K, MD2, Hendricks-Muñoz KD, Rezba C.  Transesophageal echocardiography (TEE) as a monitor of intraoperative ventricular volume, function and IV fluid management: impact on intra and postoperative fluid management in the partial separation of conjoined twins. Society of Anesthesia Research, 2013

Mohammed T, Munoz JL, Ober J, Lewis S, Xu J, Cone S, Edmond M, Moores R, and Hendricks-Muñoz KD. Methicillin Resistant Staphylococcus Aureus (MRSA) and the individual room Neonatal Intensive Care Unit Society of Pediatrics Research, May 2013

Jurdi S, Jayaram A , Moores R, Mohammed T, Fox J, Barker G , Hendricks-Muñoz KD. Children’s Hospital of Richmond at VCU, Richmond, VA Sustained Quality Improvement initiatives improve neonatal morbidities in premature infants -an institutional experience Society of Pediatrics Research, May 2013

Mohammed T, Munoz JL, Ober J, Lewis S, Xu J, Cone S, Edmond M, Moores R, and Hendricks-Muñoz KD. Methicillin Resistant Staphylococcus Aureus (MRSA) and the individual room Neonatal Intensive Care Unit Eastern Society of Pediatrics Research, Philadelphia, Mar 2013

Fox J, Mohammed T, Moores R,  Jayaram A, Cone S, Barker G, and Hendricks-Muñoz KD. Getting to Zero: Development of a NEC QI initiative to decrease progression in NEC severity. Eastern Society of Pediatrics Research, Philadelphia, Mar 2013

Hoang T, Mally PV, Xu J, Hendricks-Muñoz KD*. Salivary cytokine analysis in preterm infants: Relationship to early delivery and levels in the well Full term infant. Society of Pediatrics Research May, 2013.

Mohammed T, Muñoz JL, Ober J, Lewis S, Xu J, Cone S, Edmond M, Moores R, and Hendricks-Muñoz KD. Methicillin Resistant Staphylococcus Aureus (MRSA) and the individual room Neonatal Intensive Care Unit Society of Pediatrics Research Society of Pediatrics Research May, 2013.

Bailey SM, Hendricks-Muñoz, KD, Mally P. Cerebro-splanchnic oxygen ration (CSOR) values in healthy term infants as measured by near-infrared spectroscopy (NIRS) Society of Pediatrics Research Society of Pediatrics Research May, 2013.

Book chapters

Wachtel E and Hendricks-Munoz KD*. Management of the Asphyxiated Newborn in Current Problems in Pediatric and Adolescent Health Care 2011 May-Jun; 41(5):132-53.

Hendricks-Muñoz KD and Prendergast CC. Family Centered and Developmental Care: Improving  Outcome in the NICU, in Neonatal Secrets 3rd Edition, Richard A Polin and Alan R Spitzer Editors, Mosby Elsevier Publishers, 2013

Mally P and Hendricks-Muñoz KD*. Late Preterm Infant: Clinical Decision Support: Pediatrics, edited by McMillan, Barrett, Boney, and Jones, 2013; online reference.

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

Lab members:
Amy S Miner (laboratory manager)
MaryEllen Dolat, M.D. (urology resident)
Yi Huang, M.D., Ph.D. (postdoc)
Tolu Makinde, Ph.D. (postdoc)
Victoria Locke (master's student)
Bharti Sharma (undergrad researcher)
Harrison Sun (undergrad researcher)

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:

A new and automated method for objective analysis of detrusor rhythm during the filling phase. Klausner AP, King AB, Byrne MD, Habibi JR, Li K, Sabarwal V, Speich JE, Ratz PH. World J Urol. 2013 Apr 30. PMID: 23633125

Fourier transform analysis of rabbit detrusor autonomous contractions reveals length dependent increases in tone and slow wave development at long lengths. Byrne MD, Klausner AP, Speich JE, Southern JB, Habibi JR, Ratz PH. J Urol. 2013 Jul;190(1):334-40. PMID: 23485511

Elevated steady-state bladder preload activates myosin phosphorylation: detrusor smooth muscle is a preload tension sensor. Southern JB, Frazier JR, Miner AS, Speich JE, Klausner AP, Ratz PH. Am J Physiol Renal Physiol. 2012 Dec 1;303(11):F1517-26. PMID: 22993074

Carbachol-induced volume adaptation in mouse bladder and length adaptation via rhythmic contraction in rabbit detrusor. Speich JE, Wilson CW, Almasri AM, Southern JB, Klausner AP, Ratz PH. Ann Biomed Eng. 2012 Oct;40(10):2266-76. PMID: 22614640

Adjustable passive stiffness in mouse bladder: regulated by Rho kinase and elevated following partial bladder outlet obstruction. Speich JE, Southern JB, Henderson S, Wilson CW, Klausner AP, Ratz PH. Am J Physiol Renal Physiol. 2012 Apr 15;302(8):F967-76. PMID: 22205227

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

Active tension adaptation at a shortened arterial muscle length: inhibition by cytochalasin-D. Bednarek ML, Speich JE, Miner AS, Ratz PH. Am J Physiol Heart Circ Physiol. 2011 Apr;300(4):H1166-73. Epub 2011 Jan 14. PMID: 21239639

ROK controls urethral tone, but by what mechanism? Ratz PH. Am J Physiol Renal Physiol. 2011 Jan;300(1):F71-2. PMID: 20962113

Failure of Bay K 8644 to induce RhoA kinase-dependent calcium sensitization in rabbit blood vessels. Alvarez SM, Miner AS, Browne BM, Ratz PH. Br J Pharmacol. 2010 Jul;160(6):1326-37. PMID: 20590624

COX Inhibitors and Overactive Bladder: The Potential for Future Therapy. Ratz PH, Speich JE and Klausner AP. Curr Bladder Dysfunct Rep. 2010 5:4-12

Length adaptation of the passive-to-active tension ratio in rabbit detrusor. Almasri AM, Ratz PH, Speich JE. Ann Biomed Eng. 2010 Aug;38(8):2594-605. Epub 2010 Apr 13. PMID: 20387122

Evidence that actomyosin cross bridges contribute to "passive" tension in detrusor smooth muscle. Ratz PH, Speich JE. Am J Physiol Renal Physiol. 2010 Jun;298(6):F1424-35. Epub 2010 Apr 7. PMID: 20375119

Rhythmic contraction generates adjustable passive stiffness in rabbit detrusor. Almasri AM, Ratz PH, Bhatia H, Klausner AP, Speich JE. J Appl Physiol. 2010 Mar;108(3):544-53. Epub 2010 Jan 7. PMID: 20056849

Adaptation of the length-active tension relationship in rabbit detrusor. Speich JE, Almasri AM, Bhatia H, Klausner AP, Ratz PH. Am J Physiol Renal Physiol. 2009 Oct;297(4):F1119-28. Epub 2009 Aug 12. PMID: 19675182

Calcium-independent phospholipase A2 participates in KCl-induced calcium sensitization of vascular smooth muscle. Ratz PH, Miner AS, Barbour SE. Cell Calcium. 2009 Jul;46(1):65-72. Epub 2009 May 31. PMID: 19487023

Potentiation of carbachol-induced detrusor smooth muscle contractions by beta-adrenoceptor activation. Klausner AP, Rourke KF, Miner AS, Ratz PH. Eur J Pharmacol. 2009 Mar 15;606(1-3):191-8. Epub 2009 Jan 29. PMID: 19374847

Potential for control of detrusor smooth muscle spontaneous rhythmic contraction by cyclooxygenase products released by interstitial cells of Cajal. Collins C, Klausner AP, Herrick B, Koo HP, Miner AS, Henderson SC, Ratz PH. J Cell Mol Med. 2009 Sep;13(9B):3236-50. Epub 2009 Feb 20. PMID: 19243470

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

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

Lab members:
Jennifer Bradley, lab manager

Current projects:

Innate Immune Function in Newborn Type I 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 potential role of Type I alveolar epithelial cells and the role of prematurity in damage-mediated inflammation. Type I cells cover the vast majority of surface area in the lung. They are exposed to environmental stimuli and are susceptible to injury from hyperoxia for example. Previously thought to be terminally differentiated and only involved in gas and water/solute exchange, recent work in adult rats have demonstrated their capacity to produce chemokines and other inflammatory mediators. We are isolating Type I cells from one day old mice and comparing their inflammatory response to cells from adult mice. In addition, we are investigating the in vitro proliferation capacity of newborn Type I cells. Since these cells express high levels of RAGE receptors, and are the only pulmonary cell line that have RAGE receptors, we are also investigating if the inflammatory response in Type I cells is mediated through RAGE.

Recent publications:

Aucott SW, Watterberg KL, Shaffer ML, Donohue PK, PROPHET study group Early cortisol values and long-term outcomes in extremely low birth weight infants. J Perinatol. 2010;30:484-8. Read more

Tanabe T, Kanoh S, Rozycki HJ, Rubin BK. Cardiac asthma: New insights into an old disease. Expert Rev Respir Med. 2012;6:705-14. Read more

Rozycki HJ, Zhao W. Interleukins for the paediatric pulmonologist. Paediatric Respiratory Reviews 2014 ;15:56-68. Read more

Hoffer-Schaefer A, Rozycki HJ, Yopp M, Brock A, Rubin BK. Guaifenesin does not improve symptoms or change the properties of sputum in persons with acute respiratory tract infection. Respir Care. 2014 May;59(5):631-6. doi: 10.4187/respcare.02640. Read more

Rozycki  HJ. Potential contribution of Type I lung epithelial cells to chronic neonatal lung disease Front. Pediatr. doi: 10.3389/fped.2014.00045. Read more

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

Lab members:
Isao Suzaki, M.D., Ph.D., postdoctoral fellow
Shuichi Kawano, M.D., Ph.D, postdoctoral fellow
Kosaku Komiya, M.D., Ph.D., postdoctoral fellow
Michael Davis, RRT, graduate student
Navami Ravindra, engineering research student
Jonathan Ma M.D., pediatric research resident

Current projects:

• The goblet cell as an immune effector cell in the airway
• Aerosol dapsone for therapy of inflammatory airway diseases
• CF nasal microbiome and effect of antibiotics delivered as nasal aerosols
• Difference in inflammatory and immune response comparing nasal and bronchial epithelia in culture
• Longitudinal changes in CF sputum properties, inflammation, and pulmonary function
• Airway squamous metaplasia and transforming growth factor beta
• Airway disease in persons with ichthyosis and potential therapies
• The International plastic bronchitis registry to investigate the natural history and potential therapies for plastic bronchitis
• Anticholinergic medications as potential airway immunomodulators
• Aerosol therapy and the patient-device interface
• Effect of nocturnal nasal humidification and flow on recovery from an exacerbation of CF airway disease
• Airway Tissue Factor expression in inflammatory airway diseases
• Periostin, interleukin 13, and severe asthma

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.

Recent publications:

Rubin BK, Priftis KN, Schmidt HJ, Henke MO. Secretory hyperresponsiveness and pulmonary mucus hypersecretion. Chest 2014;146:496-507. Read more

Rubin BK, Williams RW. Emerging aerosol drug delivery strategies: From bench to clinic. Adv Drug Deliv Rev 2014 doi: 10.1016/j.addr.2014.06.008. Read more

Strickland SL, Rubin BK, Drescher GS, Haas CF, O'Malley CA, Volsko TA, et al. AARC clinical practice guideline: effectiveness of nonpharmacologic airway clearance therapies in hospitalized patients. Respir Care 2013;58:2187-93. Read more

Tanabe T, Kanoh S, Moskowitz WB, Rubin BK. Cardiac asthma: transforming growth factor-beta from the failing heart leads to squamous metaplasia in human airway cells and in the murine lung. Chest 2012;142:1274-83. Read more

Tanabe T, Rozycki HJ, Kanoh S, Rubin BK. Cardiac asthma: new insights into an old disease. Expert Rev Respir Med 2012;6:705-14. Read more

Tanabe T, Shimokawaji T, Kanoh S, Rubin BK. IL-33 stimulates CXCL8/IL-8 secretion in goblet cells but not normally differentiated airway cells. Clin Exp Allergy 2014;44:540-52. Read more

Teves ME, Zhang Z, Costanzo RM, Henderson SC, Corwin FD, Zweit J, Sundaresan G, Subler M, Salloum FN, Rubin BK, Strauss JF 3rd. Sperm-associated antigen-17 gene is essential for motile cilia function and neonatal survival. Am J Respir Cell Mol Biol 2013;48:765-72. Read more

Tokita E, Tanabe T, Asano K, Suzaki H, Rubin BK. Club cell 10-kDa protein attenuates airway mucus hypersecretion and inflammation. Eur Respir J 2014 pii: erj00809-2013. Read more

Nicola ML, Carvalho HB, Yoshida CT, Anjos FM, Nakao M, Santos Ude P, Cardozo KH, Carvalho VM, Pinto E, Farsky SH, Saldiva PH, Rubin BK, Nakagawa NK. Young "healthy" smokers have functional and inflammatory changes in the nasal and the lower airways. Chest. 2014;145:998-1005. Read more

McNamara DG, Asher MI, Rubin BK, Stewart A, Byrnes CA. Heated humidification improves clinical outcomes, compared to a heat and moisture exchanger in children with tracheostomies. Respir Care. 2014;59:46-53. Read more

Dodson KM, Cohen RS, Rubin BK . Middle ear fluid characteristics in pediatric otitis media with effusion. Int J Pediatr Otorhinolaryngol. 2012;76:1806-09. Read more

Principal investigator:
Judith A. Voynow, MD

Lab members:
Shuo Zheng, Ph.D.
Apparao Kummarapurugu Ph.D.

Current projects:

• NQO1: Linking Oxidant Stress to Inflammation in Airway Epithelial Cells [R01ES016836]
• Inhaled 2-O, 3-O Desulfated Heparin for Cystic Fibrosis [pending BrIDGS]
• Environmental Influences on the Microbiome in Neonates [pending R21]
• Mucin MUC5AC Regulatory Domains

Research interests:

We have focused on investigating the pathogenesis of some of the most challenging problems in pediatric pulmonology:

• Ozone is a major air pollutant in urban centers that causes exacerbations of chronic respiratory diseases such as asthma and COPD. However, there are differences in individual responses to ozone related to host factors. We are investigating the mechanism underlying the epidemiologic observation that patients homozygous for a polymorphism in NADPH Quinone Oxidoreductase 1 (NQO1), are protected from both inflammation and airflow obstruction following ozone exposure. Using both murine and human model systems, we have discovered that the presence or absence of NQO1 regulates generation of isoprostanes that increase susceptibility or block susceptibility to ozone.
• Cystic fibrosis patients are plagued by chronic infection and neutrophilic inflammation which drives the relentless progression of airway disease leading to respiratory failure. We have been investigating how a major inflammatory mediator in the CF lung, neutrophil elastase, triggers a cascade of signaling resulting in persistent inflammation and mucous cell hypertrophy and mucus secretion. We are currently developing a potential new inhaled multifunction therapy for CF, O-desulfated heparin, which has potent anti-protease and anti-inflammatory properties with minimal anti-coagulant activity.
• Bronchopulmonary dysplasia is a major cause of morbidity in very early preterm infants however, biomarkers for lung disease development are not known. In collaboration with Dr. Karen Hendricks-Munoz, we propose to investigate in a murine model, whether maternal exposures to ambient air pollutants (diesel exhaust), alter the maternal and neonatal microbiome resulting in increased risk for inflammation and airflow obstruction in the offspring.
• Mucins are the major macromolecular constituents of mucus and have important antimicrobial and anti-inflammatory functions at epithelial surfaces. We have been studying the molecular domains of MUC5AC, a major respiratory tract mucin to determine how it is regulated by inflammation and neutrophil elastase. We recently submitted a report of the previously unknown genomic sequence of the major tandem repeat domain of MUC5AC which will be an important contribution to understanding individual differences in translated protein and potentially in identifying new domains of regulation at the genomic level.

Recent publications:

• Voynow JA and Kummarapurugu A (2011) Isoprostanes and Asthma, BBA, 1810: 1091-1095, PMID: 21596100.
• Fischer, BM, Pavlisko, E, and Voynow JA (2011) Pathogenic Triad in COPD: Oxidative Stress, Protease-Antiprotease Imbalance and Inflammation, Int. J. COPD, 6:413-421. PMID: 21857781
• Meyer ML, Potts-Kant EN, Ghio AJ, Fischer BM, Foster WM, and Voynow JA (2012) NAD(P)H quinone oxidoreductase 1 regulates neutrophil elastase-induced mucus cell metaplasia, Am. J. Physiol. Lung Cell Mol. Physiol., 303: L181-188, PMID: 22659878.
• Kummarapurugu AB, Fischer BM, Zheng S, Milne GL, Ghio AJ, Potts-Kant EN, Foster WM, Soderblom EJ, Dubois LG, Moseley MA, Thompson JW, Voynow JA (2012) NADPH Quinone Oxidoreductase 1 Regulates Host Susceptibility to Ozone via Isoprostane Generation, J. Biol. Chem., 288:4681-91, PMID: 23275341.
• Fischer BM, Wong JK, Degan S, Kummarapurugu AB, Zheng S, Haridass P, Voynow, JA (2013) Increased expression of senescence markers in cystic fibrosis airways, Am J Physiol Lung Cell Mol Physiol, 304:L394-400, PMID: 23316069
• Ghio, AJ, Soukup, JM, Richards, JH, Fischer, BM, Voynow, JA, Schmechel, DE (2013) Deficiency of α-1-antitrypsin influences systemic iron homeostasis, International Journal of COPD, 8: 45–51; PMID: 23378755
• Park JA, Sharif AS, Shiomi T, Kobzik L, Kasahara DI, Tschumperlin DJ, Voynow JA, Drazen JM.(2013) Human neutrophil elastase-mediated goblet cell metaplasia is attenuated in TACE-deficient mice, Am J. Physiol. Lung Cell Mol. Physiol., in press, PMID:23564510
• Voynow JA, Mascarenhas MR, Kelly A and Scanlin TF, (2012) “Cystic Fibrosis,” In: Clinical Decision Support: Pulmonary Medicine and Sleep Disorders, eds. M. Grippi,  J. Heffner, R. Kotloff, Decision Support in Medicine, LLC, Wilmington, DE.
• Egan ME, Green D, Voynow JA (2013) “Cystic Fibrosis,” in Nelson Textbook of Pediatrics 20th Edition, In press.
• Voynow JA, Scanlin TF, Kelly A, Mascarenhas M (2013) “Cystic Fibrosis” in Fishman’s Pulmonary Diseases and Disorders, in press.

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

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

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.