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Director: Wanda K. O’Neal, PhD; Co-Director: Alessandra Livraghi-Butrico, PhD

Introduction

The Marsico Lung Institute/UNC Cystic Fibrosis Center Animal Models Core is dedicated to providing access for collaborating scientists to animal models (primarily mouse) critical for in vivo studies that provide insights into pulmonary disease pathophysiology and treatment. The Animal Models Core has been involved in the generation and/or study of over 25 lines of transgenic or knockout mice for a variety of collaborators over the years. The development of new transgenic of knockout lines is highly dependent upon a collaboration with the UNC Transgenic Mouse Core, and more recently to the use of transgenic lines obtained from international resources, such as KOMP, EUCOMM, and the MRRCC. Publications utilizing these mouse models in a variety of context can be found here.

Currently, the Animal Models Core supports research covering many aspects of lung disease biology, including mucus obstruction leading to pathology, viral pathogenesis, injury/repair, and inflammation. The Animal Models Core laboratory is located on the seventh floor of Marsico Hall, with most of the mice housed in Genetic Medicine.

One of the more successful mouse lines to be developed in collaboration with the Animal Models Core is the Scnn1b-Tg mouse that provides a valuable model for muco-obstructive lung diseases, such as CF, COPD, and chronic bronchitis. This mouse has been widely used to explore features of pulmonary disease physiology and treatment since its development in 2004, and the number of publications based upon this model continues to grow.

The Animal Models Core Laboratory also provides support and expertise for mouse colony maintenance, breeding strategies, mouse lung phenotyping protocols, and submission of Applications to Use Live Vertebrate Animals to maintain compliance with IACUC guidelines. Particularly valuable are the phenotyping services, which include collection of lavage samples for cytokines, mucins, microbiology, and inflammatory cell counts. Histological sections can also be obtained that can be used to quantify specific aspects of pulmonary pathology, including emphysema, mucus plugging, inflammation, and goblet cell metaplasia. Collaborations with other Marsico Lung Institute scientists, such as Drs. Barbara Grubb and Martina Gentzsch, extend the phenotyping to specialized measures of mucociliary clearance and ion transport properties.

Personnel

Wanda O'Neal
Wanda O’Neal, PhD
Associate Professor
woneal@med.unc.edu
Director
Alessandra Livraghi-Butrico
Alessandra Livraghi-Butrico, PhD
Associate Professor
Alessandra_livraghi@med.unc.edu
Co-Director
Mrs. Allison Volmer, BS
Mrs. Allison Volmer, BS
Research Specialist
Mrs. Allison Volmer, BS
Research Specialist

Allison joined the Animal Models Lab in January of 2010. Allison graduated from Texas A&M University where she obtained a Bachelor’s of Science in Biomedical Science in 1995. Before moving to Chapel Hill, she worked at the Baylor College of Medicine and The University of Texas- Medical Branch for Dr. Paul Overbeek in Molecular Biology and Dr. Neal Waxham in Neurobiology respectively. She is responsible for colony management and genotyping of Mucin-deficient deficient βENaC-Tg mice as well as Rag deficient, SPDEF, and many others and she participates in phenotyping efforts.

Contact Information

125 Mason Farm Road
The University of North Carolina at Chapel Hill
Campus Box #7248
Chapel Hill, NC 27599
Phone: (919) 843-1097
Fax: (919) 966-5178
Email: woneal@med.unc.edu
Email: alessandra_livraghi@med.unc.edu

Core Publications:

  1. Xu J, Livraghi-Butrico A, Hou X, Rajagopalan C, Zhang J, Song J, Jiang H, Wei HG, Wang H, Bouhamdan M, Ruan J, Yang D, Qiu Y, Youming X, Barrett RP, McClellan SA, Mou H, Wu Q, Chen X, Rogers TD, Wilkinson KJ, Gilmore RC, Esther CR Jr, Zaman K, Liang X, Sobolic M, Hazlett L, Zhang K, Frizzell RA, Gentzsch M, O’Neal WK, Grubb BR, Chen YE, Boucher RC, Sun F. Phenotypes of CF rabbits generated by CRISPR/Cas9-mediated disruption of the CFTR gene. JCI Insight. 2021 Jan 11;6(1):e139813. doi: 10.1172/jci.insight.139813. PMID: 33232302. PMCID: PMC7821608.
  2. Chen G, Volmer AS, Wilkinson KJ, Deng Y, Jones LC, Yu D, Bustamante-Marin XM, Burns KA, Grubb BR, O’Neal WK, Livraghi-Butrico A, Boucher RC. Role of Spdef in the regulation of Muc5b expression in the airways of naïve and muco-obstructed mice. Am J Respir Cell Mol Biol. 2018 Sep;59(3):383-396. doi: 10.1165/rcmb.2017-0127OC. PMID: 29579396. PMCID: PMC6189647.
  3. Saini Y, Lewis B, Yu D, Dang H, Livraghi-Butrico A, Del Piero F, O’Neal W, Boucher R. Effect of LysM+ macrophage depletion on lung pathology in mice with chronic bronchitis. Physiol Rep. 2018 Apr;6(8):e13677. doi: 10.14814/phy2.13677. PMID: 29667749. PMCID: PMC5904692.
  4. Livraghi-Butrico A, Wilkinson K, Volmer A, Gilmore R, Rogers T, Caldwell R, Burns K, Esther C Jr., Mall M, Boucher R, O’Neal W, Grubb B. Lung disease phenotypes caused by over-expression of combinations of alpha, beta, and gamma subunits of the epithelial sodium channel in mouse airways. Am J Physiol Lung Cell Mol Physiol. 2018 Feb 1;314(2):L318-L331. doi: 10.1152/ajplung.00382.2017. PMID: 29074490. PMCID: PMC5866504.
  5. Rowson-Hodel AR, Wald JH, Hatakeyama J, O’Neal WK, Stonebraker JR, VanderVorst K, Saldana MJ, Borowsky AD, Sweeney C, Carraway KL 3rd. Membrane Mucin Muc4 promotes blood cell association with tumor cells and mediates efficient metastasis in a mouse model of breast cancer. Oncogene. 2018 Jan 11;37(2):197-207. doi: 10.1038/onc.2017.327. PMID: 28892049. PMCID: PMC5930013.
  6. 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 Immunol. 2017 Mar;10(2):395-407. doi: 10.1038/mi.2016.63. PMID: 27435107. PMCID: PMC5250616.
  7. 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. Am J Respir Cell Mol Biol. 2016 Feb;54(2):210-21. doi: 10.1165/rcmb.2014-0111OC. PMID: 26121027; PMCID: PMC4821038.
  8. Yu D, Davis RM, Aita M, Burns KA, Clapp PW, Gilmore RC, Chua M, O’Neal WK, Schlegel R, Randell SH, C Boucher R. Characterization of Rat Meibomian Gland Ion and Fluid Transport. Invest Ophthalmol Vis Sci. 2016 Apr 1;57(4):2328-43. doi: 10.1167/iovs.15-17945. PMID: 27127933; PMCID: PMC4855829.
  9. Saini Y, Dang H, Livraghi-Butrico A, Kelly EJ, Jones LC, O’Neal WK, Boucher RC. Gene expression in whole lung and pulmonary macrophages reflects the dynamic pathology associated with airway surface dehydration. BMC Genomics. 2014 Sep 10;15(1):726. doi: 10.1186/1471-2164-15-726. PMID: 25204199; PMCID: PMC4247008.
  10. Sesma JI, Kreda SM, Okada SF, van Heusden C, Moussa L, Jones LC, O’Neal WK, Togawa N, Hiasa M, Moriyama Y, Lazarowski ER. Vesicular nucleotide transporter regulates the nucleotide content in airway epithelial mucin granules. Am J Physiol Cell Physiol. 2013 May 15;304(10):C976-84. doi: 10.1152/ajpcell.00371.2012. Erratum in: Am J Physiol Cell Physiol. 2014 Feb 15;306(4):C415. PMID: 23467297; PMCID: PMC3651637.
  11. 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. Am J Physiol Lung Cell Mol Physiol. 2013 Apr 1;304(7):L469-80. doi: 10.1152/ajplung.00150.2012. PMID: 23377346; PMCID: PMC3627939.
  12. 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. doi: 10.1038/nature12807. PMID: 24317696; PMCID: PMC4001806.
  13. Livraghi-Butrico A, Kelly EJ, Klem ER, Dang H, Wolfgang MC, Boucher RC, Randell SH, O’Neal WKMucus clearance, MyD88-dependent and MyD88-independent immunity modulate lung susceptibility to spontaneous bacterial infection and inflammation. Mucosal Immunol. 2012 Jul;5(4):397-408. doi: 10.1038/mi.2012.17. PMID: 22419116; PMCID: PMC3377774.
  14. 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. Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):16528-33. doi: 10.1073/pnas.1206552109. Erratum in: Proc Natl Acad Sci U S A. 2014 Apr 15;111(15):5753. PMID: 23012413; PMCID: PMC3478656.
  15. Livraghi-Butrico A, Grubb BR, Kelly EJ, Wilkinson KJ, Yang H, Geiser M, Randell SH, Boucher RC, O’Neal WKGenetically determined heterogeneity of lung disease in a mouse model of airway mucus obstruction. Physiol Genomics. 2012 Apr 15;44(8):470-84. doi: 10.1152/physiolgenomics.00185.2011. PMID: 22395316; PMCID: PMC3339860.
  16. Jones LC, Moussa L, Fulcher ML, Zhu Y, Hudson EJ, O’Neal WK, Randell SH, Lazarowski ER, Boucher RC, Kreda SM. VAMP8 is a vesicle SNARE that regulates mucin secretion in airway goblet cells. J Physiol. 2012 Feb 1;590(3):545-62. doi: 10.1113/jphysiol.2011.222091. PMID: 22144578; PMCID: PMC3379700.
  17. Grubb BR, O’Neal WK, Ostrowski LE, Kreda SM, Button B, Boucher RC. Transgenic hCFTR expression fails to correct β-ENaC mouse lung disease. Am J Physiol Lung Cell Mol Physiol. 2012 Jan 15;302(2):L238-47. doi: 10.1152/ajplung.00083.2011. PMID: 22003093; PMCID: PMC3349361.
  18. Nguyen Y, Procario MC, Ashley SL, O’Neal WK, Pickles RJ, Weinberg JB. Limited effects of Muc1 deficiency on mouse adenovirus type 1 respiratory infection. Virus Res. 2011 Sep;160(1-2):351-9. doi: 10.1016/j.virusres.2011.07.012. PMID: 21816184; PMCID: PMC3163747.
  19. Seminario-Vidal L, Okada SF, Sesma JI, Kreda SM, van Heusden CA, Zhu Y, Jones LC, O’Neal WK, Penuela S, Laird DW, Boucher RC, Lazarowski ER. Rho signaling regulates pannexin 1-mediated ATP release from airway epithelia. J Biol Chem. 2011 Jul 29;286(30):26277-86. doi: 10.1074/jbc.M111.260562. PMID: 21606493; PMCID: PMC3143590.
  20. 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. J Biol Chem. 2010 Aug 27;285(35):26945-26955. doi: 10.1074/jbc.M110.151803. PMID: 20566636; PMCID: PMC2930694.
  21. Ostrowski LE, Yin W, Rogers TD, Busalacchi KB, Chua M, O’Neal WK, Grubb BR. Conditional deletion of dnaic1 in a murine model of primary ciliary dyskinesia causes chronic rhinosinusitis. Am J Respir Cell Mol Biol. 2010 Jul;43(1):55-63. doi: 10.1165/rcmb.2009-0118OC. PMID: 19675306; PMCID: PMC2911571.
  22. 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 {beta}-epithelial Na+ channel-overexpressing mice: role of TNF-{alpha} and IL-4R{alpha} signaling, influence of neonatal development, and limited efficacy of glucocorticoid treatment. J Immunol. 2009 Apr 1;182(7):4357-67. doi: 10.4049/jimmunol.0802557. PMID: 19299736; PMCID: PMC2659461.
  23. 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. Am J Respir Crit Care Med. 2008 Oct 15;178(8):822-31. doi: 10.1164/rccm.200712-1894OC. PMID: 18658107; PMCID: PMC2566793.
  24. 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. Am J Respir Crit Care Med. 2008 Apr 1;177(7):730-42. doi: 10.1164/rccm.200708-1233OC. PMID: 18079494; PMCID: PMC2277210.
  25. Ostrowski LE, Yin W, Diggs PS, Rogers TD, O’Neal WK, Grubb BR. Expression of CFTR from a ciliated cell-specific promoter is ineffective at correcting nasal potential difference in CF mice. Gene Ther. 2007 Oct;14(20):1492-501. doi: 10.1038/sj.gt.3302994. PMID: 17637798.
  26. 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. J Virol. 2004 Dec;78(24):13755-68. doi: 10.1128/JVI.78.24.13755-13768.2004. PMID: 15564484; PMCID: PMC533903.
  27. Okada SF, O’Neal WK, Huang P, Nicholas RA, Ostrowski LE, Craigen WJ, Lazarowski ER, Boucher RC. Voltage-dependent anion channel-1 (VDAC-1) contributes to ATP release and cell volume regulation in murine cells. J Gen Physiol. 2004 Nov;124(5):513-26. doi: 10.1085/jgp.200409154. PMID: 15477379; PMCID: PMC2234005.
  28. Mall M, Grubb BR, Harkema JR, O’Neal WK, Boucher RC. Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice. Nat Med. 2004 May;10(5):487-93. doi: 10.1038/nm1028. PMID: 15077107.
  29. Zariwala M*, O’Neal WK*, Noone PG, Leigh MW, Knowles MR, Ostrowski LE. Investigation of the possible role of a novel gene, DPCD, in primary ciliary dyskinesia. Am J Respir Cell Mol Biol. 2004 Apr;30(4):428-34. doi: 10.1165/rcmb.2003-0338RC. PMID: 14630615. *authors contributed equally to manuscript.
  30. Ostrowski LE, Hutchins JR, Zakel K, O’Neal WK. Targeting expression of a transgene to the airway surface epithelium using a ciliated cell-specific promoter. Mol Ther. 2003 Oct;8(4):637-45. doi: 10.1016/s1525-0016(03)00221-1. PMID: 14529837.