Wanda O'Neal, PhD

Research Associate Professor

Specialty Areas: Molecular Genetics

Research Focus:

I received my PhD in 1993 from Baylor College of Medicine in the Department of Human and Molecular Genetics under the direction of Dr. Arthur Beaudet. During my first year at Baylor, the cystic fibrosis (CF) gene was discovered, and my career path was set. Under Dr. Beaudet’s direction, I was one of the first to report a population-based study on what turned out to be the most common cystic fibrosis mutation, F508del (1). Baylor College of Medicine was also one of the first institutions to make broad use of recombination in embryonic stem cells for generating mouse lines, and for the bulk of my graduate thesis, in collaboration with Dr. Allen Bradley’s group, I was one of several investigators worldwide who successfully generated mice carrying CF gene mutations (2-4). After graduating, I spent the next five years completing a post-doctoral fellowship, again with Dr. Beaudet, evaluating the potential to utilize adenoviral-based vectors for gene transfer in CF (5-10). While the use of adenoviral vectors in clinical trials for gene transfer have not advanced, the experiences at Baylor provided a solid and broad training in molecular biology, human genetics, mouse transgenics and phenotyping, and viral vector use, all of which prepared me for my academic career.

In 1998, I joined the University of North Carolina Cystic Fibrosis Center (now the Marsico Lung Institute/UNC CF Center) as director of the Molecular Biology and Mouse Core, a position that I still hold. It has been a huge honor to serve in this position. The Molecular Biology and Mouse Core provides the molecular biology (DNA cloning, RNA isolation and analysis, gene editing (CRISPR/Cas9) service), mouse model production, mouse model genotyping and phenotyping for collaborating scientists at UNC and outside investigators as needed. Since 1998, the Core has consistently contributed to the overall group by providing needed expertise, reagents, and equipment in molecular biology and mouse colony management. The Molecular Biology and Mouse Core has been, and continues to be, supported by the NHLBI, NIDDK, Cystic Fibrosis Foundation through a variety of mechanisms related to large collaborative efforts, including PPG Core Grant funding, the NIDDK-supported MTCC and CFRTCC, and the CFF Research and Development Program (RDP).

Throughout its history, the Molecular Biology Core has sought to keep up with the ever-present technological advances. Over the years, not only has the Core conducted standard cloning, PCR, RNA analysis, we have worked with investigators to develop expertise in gene expression microarrays, RNAsequencing, siRNA technologies, CRISPR/Cas9, and now are providing RNA in situ hybridization via the RNAScope technology. The success of the Core is highlighted by the broad range of publications supported by the Core (See bibliography; provide my Bibliography link) and the large number of grants that have utilized Core services to generate key preliminary data to ensure the success of the project. Continued funding by the granting agencies for services provided by is also a measure of the Core’s productivity. The services provided by the Core are also now and integral and important aspect of the work provided by SPIROVATION (http://www.spirovation.com/).

In addition to providing Core services, Dr. O’Neal also has had the ability to pursue independent lines of research in collaboration with Marsico Lung Institute scientists. Particularly rewarding are the research efforts focused on understanding the gene modifiers that associate with CF phenotypes (11-16), expanding the utility of theScnn1b-Tg mouse model for muco-obstructive lung disease (17-25); see Mouse Core for more information), and the understanding of mucin biology and genetics (26-30). While Dr. O’Neal’s true passion is CF research (http://news.unchealthcare.org/news/2015/april/the-family-disease), the environment in the Marsico Lung Institute has allowed her to apply her skills and expertise to a variety of related problems, including general airway cell biology and physiology and chronic obstructive pulmonary disease, primarily though involvement in the SPIROMICS study (31-33)(http://www.spirovation.com/) where she serves as Chair of the Biomarkers Working Group.

In the UNC Health Care and School of Medicine Newsroom, the article entitled: “The Family Disease” was published in April, 2015, and describes Dr. O’Neal’s path to research.

Dr. O’Neal’s CV can be viewed here.

Selected Bibliography:

  1. Donoghue LJ*, Livraghi-Butrico A*, McFadden KM, Thomas JM, Chen G, Grubb BR, O’Neal WK, Boucher RC, Kelada SNP. Identification of trans protein QTL for secreted airway mucins in mice and a causal role for Bpifb1. Genetics 2017 Oct;207(2):801-812. doi: 10.1534/genetics.117.300211.
  2. Kesimer M, Ford AA, Ceppe A, Radicioni G, Cao R, Davis WC, Doerschuk CM, Alexis NE, Anderson WH, Henderson AG, Barr G, Bleecker ER, Christenson SA, Cooper CB, Han MLK, Hansel NN, Hastie AT, Hoffman EA, Kanner RE, Martinez F, Paine R, Woodruff PG, O’Neal WK, Boucher RC. Airway mucin concentration as a marker of chronic bronchitis. New England Journal of Medicine 2017 Sep 7;377(10):911-922. doi: 10.1056/NEJMoa1701632. PMID: 28877023.
  3. Polineni D, Dang H, Jones L, Gallins P, Pace R, Stonebraker J, Commander L, Krenicky J, Zhou Y, Corvol H, Cutting G, Drumm M, Strug L, Boyle M, Durie P, Chmiel J, Zou F, Wright F, O’Neal W, Knowles M. Airway mucosal host defense is key to genomic regulation of cystic fibrosis lung disease severity. American Journal of Respiratory and Critical Care Medicine 2017 Aug 30. doi: 10.1164/rccm.201701-0134OC. [Epub ahead of print].
  4. Livraghi-Butrico A, Grubb BR, Wilkinson K, Volmer AS, Burns KA, Evans C, O’Neal WK, Boucher RC. Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease. Mucosal Immunology 2017 Mar;10(2):395-407. doi: 10.1038/mi.2016.63. PMID: 27435107. PMCID: PMC5250616.
  5. Corvol H, Blackman SM, Boelle PY, Gallins PJ, Pace RG, Stonebraker JR, Accurso FJ, Clement A, Collaco JM, Dang H, Dang AT, Franca A, Gong J, Guillot L, Keenan K, Li W, Lin F, Patrone MV, Raraigh KS, Sun L, Zhou YH, O’Neal WK, Sontag MK, Levy H, Durie PR, Rommens JM, Drumm ML, Wright FA, Strug LJ, Cutting GR, Knowles MR. Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis. Nature Communications 2015;6:8382.
  6. Freeman CM, Crudgington S, Stolberg VR, Brown JP, Sonstein J, Alexis NE, Doerschuk CM, Basta PV, Carretta EE, Couper DJ, Hastie AT, Kaner RJ, O’Neal WK, Paine R, 3rd, Rennard SI, Shimbo D, Woodruff PG, Zeidler M, Curtis JL. Design of a multi-center immunophenotyping analysis of peripheral blood, sputum and bronchoalveolar lavage fluid in the subpopulations and intermediate outcome measures in copd study (spiromics). Journal of Translational Medicine 2015;13:19.
  7. O’Neal WK, Gallins P, Pace RG, Dang H, Wolf WE, Jones LC, Guo X, Zhou YH, Madar V, Huang J, Liang L, Moffatt MF, Cutting GR, Drumm ML, Rommens JM, Strug LJ, Sun W, Stonebraker JR, Wright FA, Knowles MR. Gene expression in transformed lymphocytes reveals variation in endomembrane and hla pathways modifying cystic fibrosis pulmonary phenotypes. American Journal of Human Genetics 2015;96:318-328.
  8. Saini Y, Wilkinson KJ, Terrell KA, Burns KA, Livraghi-Butrico A, Doerschuk CM, O’Neal WK, Boucher RC. Neonatal pulmonary macrophage depletion coupled to defective mucus clearance increases susceptibility to pneumonia and alters pulmonary immune responses. American Journal of Respiratory Cell and Molecular Biology 2015;54:210-221.
  9. Guo X, Pace RG, Stonebraker JR, O’Neal WK, Knowles MR. Meconium ileus in cystic fibrosis is not linked to central repetitive region length variation in muc1, muc2, and muc5ac. Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society 2014;13:613-616.
  10. Guo X, Zheng S, Dang H, Pace RG, Stonebraker JR, Jones CD, Boellmann F, Yuan G, Haridass P, Fedrigo O, Corcoran DL, Seibold MA, Ranade SS, Knowles MR, O’Neal WK, Voynow JA. Genome reference and sequence variation in the large repetitive central exon of human muc5ac. American Journal of Respiratory Cell and Molecular Biology 2014;50:223-232.
  11. O’Neal WK, Anderson W, Basta PV, Carretta EE, Doerschuk CM, Barr RG, Bleecker ER, Christenson SA, Curtis JL, Han MK, Hansel NN, Kanner RE, Kleerup EC, Martinez FJ, Miller BE, Peters SP, Rennard SI, Scholand MB, Tal-Singer R, Woodruff PG, Couper DJ, Davis SM. Comparison of serum, edta plasma and p100 plasma for luminex-based biomarker multiplex assays in patients with chronic obstructive pulmonary disease in the spiromics study. Journal of Translational Medicine 2014;12:9.
  12. Couper D, LaVange LM, Han M, Barr RG, Bleecker E, Hoffman EA, Kanner R, Kleerup E, Martinez FJ, Woodruff PG, Rennard S. Design of the subpopulations and intermediate outcomes in copd study. Thorax 2013;.
  13. Livraghi-Butrico A, Kelly EJ, Wilkinson KJ, Rogers TD, Gilmore RC, Harkema JR, Randell SH, Boucher RC, O’Neal WK, Grubb BR. Loss of cftr function exacerbates the phenotype of na+ hyperabsorption in murine airways. American Journal of Physiology: Lung Cellular and Molecular Physiology 2013;304:L469-L480.
  14. Martino MB, Jones L, Brighton B, Ehre C, Abdulah L, Davis CW, Ron D, O’Neal WK, Ribeiro CM. The er stress transducer ire1beta is required for airway epithelial mucin production. Mucosal Immunology 2013;6:639-654.
  15. Roy M, Livraghi-Butrico A, Fletcher AA, McElwee MM, Evans SE, Boerner RM, Alexander SN, Bellinghausen LK, Song AS, Petrova YM, Tuvim MJ, Adachi R, Romo I, Bordt AS, Bowden MG, Sisson JH, Woodruff PG, Thornton DJ, Rousseau K, De la Garza MM, Moghaddam SJ, Karmouty-Quintana H, Blackburn MR, Drouin SM, Davis CW, Terrell KA, Grubb BR, O’Neal WK, Flores SC, Cota-Gomez A, Lozupone CA, Donnelly JA, Watson AM, Hennessy CE, Keith RC, Yang IV, Barthel L, Henson PM, Janssen WJ, Schwartz DA, Boucher RC, Dickey BF, Evans CM. Muc5b is required for airway defense. Nature 2013;505:412-416.
  16. Ehre C, Worthington EN, Liesman RM, Grubb BR, Barbier D, O’Neal WK, Sallenave JM, Pickles RJ, Boucher RC. Overexpressing mouse model demonstrates the protective role of muc5ac in the lungs. Proceedings of the National Academy of Sciences of the United States of America 2012;109:16528-16533.
  17. Livraghi-Butrico A, Grubb BR, Kelly EJ, Wilkinson KJ, Yang H, Geiser M, Randell SH, Boucher RC, O’Neal WK. Genetically determined heterogeneity of lung disease in a mouse model of airway mucus obstruction. Physiology Genomics 2012;44:470-484.
  18. Livraghi-Butrico A, Kelly EJ, Klem ER, Dang H, Wolfgang MC, Boucher RC, Randell SH, O’Neal WK. Mucus clearance, myd88-dependent and myd88-independent immunity modulate lung susceptibility to spontaneous bacterial infection and inflammation. Mucosal Immunology 2012;5:397-408.
  19. Sun L, Rommens JM, Corvol H, Li W, Li X, Chiang TA, Lin F, Dorfman R, Busson PF, Parekh RV, Zelenika D, Blackman SM, Corey M, Doshi VK, Henderson L, Naughton KM, O’Neal WK, Pace RG, Stonebraker JR, Wood SD, Wright FA, Zielenski J, Clement A, Drumm ML, Boelle PY, Cutting GR, Knowles MR, Durie PR, Strug LJ. Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis. Nature Genetics 2012;44:562-569.
  20. Guo X, Pace RG, Stonebraker JR, Commander CW, Dang AT, Drumm ML, Harris A, Zou F, Swallow DM, Wright FA, O’Neal WK, Knowles MR. Mucin variable number tandem repeat polymorphisms and severity of cystic fibrosis lung disease: Significant association with muc5ac. PLoSOne 2011;6:e25452.
  21. Wright FA, Strug LJ, Doshi VK, Commander CW, Blackman SM, Sun L, Berthiaume Y, Cutler D, Cojocaru A, Collaco JM, Corey M, Dorfman R, Goddard K, Green D, Kent JW, Jr., Lange EM, Lee S, Li W, Luo J, Mayhew GM, Naughton KM, Pace RG, Pare P, Rommens J, Sandford A, Stonebraker JR, Sun W, Taylor C, Vanscoy LL, Zou F, Blangero J, Zielenski J, O’Neal WK, Drumm ML, Durie PR, Knowles MR, Cutting GR. Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. Nature Genetics 2011;43:539-546.
  22. Mall MA, Button B, Johannesson B, Zhou Z, Livraghi A, Caldwell RA, Schubert SC, Schultz C, O’Neal WK, Pradervand S, Hummler E, Rossier BC, Grubb BR, Boucher RC. Airway surface liquid volume regulation determines different airway phenotypes in liddle compared with betaenac-overexpressing mice. Journal of Biological Chemistry 2010;285:26945-26955.
  23. Martino MEB, Jones L, Brighton B, O’Neal WK, Ribeiro CMP. The er stress transducer ire1b is a key regulator of airway mucin production. Pediatric Pulmonology 2010;Suppl. 33 256.
  24. Livraghi A, Grubb BR, Hudson EJ, Wilkinson KJ, Sheehan JK, Mall MA, O’Neal WK, Boucher RC, Randell SH. Airway and lung pathology due to mucosal surface dehydration in á-epithelial na+ channel-overexpressing mice: Role of tnf-alpha and il-4r-alpha signaling, influence of neonatal development, and limited efficacy of glucocorticoid treatment. Journal of Immunology 2009;182:4357-4367.
  25. Mall MA, Harkema JR, Trojanek JB, Treis D, Livraghi A, Schubert S, Zhou Z, Kreda SM, Tilley SL, Hudson EJ, O’Neal WK, Boucher RC. Development of chronic bronchitis and emphysema in beta-epithelial na+ channel-overexpressing mice. American Journal of Respiratory and Critical Care Medicine 2008;177:730-742.
  26. Rowe SM, Jackson PL, Liu G, Hardison M, Livraghi A, Solomon GM, McQuaid DB, Noerager BD, Gaggar A, Clancy JP, O’Neal W, Sorscher EJ, Abraham E, Blalock JE. Potential role of high-mobility group box 1 in cystic fibrosis airway disease. American Journal of Respiratory and Critical Care Medicine 2008;178:822-831.
  27. Stonebraker JR, Wagner D, Lefensty RW, Burns K, Gendler SJ, Bergelson JM, Boucher RC, O’Neal WK, Pickles RJ. Glycocalyx restricts adenoviral vector access to apical receptors expressed on respiratory epithelium in vitro and in vivo: Role for tethered mucins as barriers to lumenal infection. Journal of Virology 2004;78:13755-13768.
  28. O’Neal WK, Rose E, Zhou H, Langston C, Rice K, Carey D, Beaudet AL. Multiple advantages of alpha-fetoprotein as a marker for in vivo gene transfer. Molecular Therapy: The Journal of the American Society of Gene Therapy 2000;2:640-648.
  29. O’Neal WK, Zhou H, Morral N, Langston C, Parks RJ, Graham FL, Kochanek S, Beaudet AL. Toxicity associated with repeated administration of first-generation adenovirus vectors does not occur with a helper-dependent vector. Molecular Medicine 2000;6:179-195.
  30. Morral N, O’Neal W, Rice K, Leland M, Kaplan J, Piedra PA, Zhou H, Parks RJ, Velji R, Aguilar-Cordova E, Wadsworth S, Graham FL, Kochanek S, Carey KD, Beaudet AL. Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons. Proceedings of the National Academy of Sciences of the United States of America 1999;96:12816-12821.
  31. O’Neal WK, Zhou H, Morral N, Aguilar-Cordova E, Pestaner J, Langston C, Mull B, Wang Y, Beaudet AL, Lee B. Toxicological comparison of e2a-deleted and first-generation adenoviral vectors expressing alpha1-antitrypsin after systemic delivery. Human Gene Therapy 1998;9:1587-1598.
  32. Morral N, O’Neal W, Zhou H, Langston C, Beaudet A. Immune responses to reporter proteins and high viral dose limit duration of expression with adenoviral vectors: Comparison of e2a wild type and e2a deleted vectors. Human Gene Therapy 1997;8:1275-1286.
  33. Zhou H, O’Neal W, Morral N, Beaudet AL. Development of a complementing cell line and a system for construction of adenovirus vectors with e1 and e2a deleted. Journal of Virology 1996;70:7030-7038
  34. Hasty P, O’Neal WK, Liu KQ, Morris AP, Bebok Z, Shumyatsky GB, Jilling T, Sorscher EJ, Bradley A, Beaudet AL. Severe phenotype in mice with termination mutation in exon 2 of cystic fibrosis gene. Somatic Cell and Molecular Genetics 1995;21:177-187.
  35. O’Neal WK, Hasty P, McCray PB, Jr., Casey B, Rivera-Perez J, Welsh MJ, Beaudet AL, Bradley A. A severe phenotype in mice with a duplication of exon 3 in the cystic fibrosis locus. Human Molecular Genetics 1993;2:1561-1569.
  36. Yorifuji T, Lemna WK, Ballard CF, Rosenbloom CL, Rozmahel R, Plavsic N, Tsui LC, Beaudet AL. Molecular cloning and sequence analysis of the murine cdna for the cystic fibrosis transmembrane conductance regulator.Genomics 1991;10:547-550.
  37. Lemna WK, Feldman GL, Kerem BT, Fernbach SD, Zevkovich EP, O’Brien WE, Riordan JR, Collins FS, Tsui LC, Beaudet AL. Mutation analysis for heterozygote detection and the prenatal diagnosis of cystic fibrosis. New England Journal of Medicine 1990;322:291-296.