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Barbara Grubb, PhD

Professor

Specialty Areas:

Ion and water transport across epithelia, Mouse Models, Cardiopulmonary Comparative Physiology

Research Focus:

  1. Ion and water transport across epithelia (primarily airway and intestinal).
  2. Use of mouse models for ion transport study.
  3. Comparative physiology (cardiopulmonary).

Alterations in transepithelial salt (and thus water) absorption and secretion result in a number of fatal or debilitating diseases in variety of epithelial tissues. In airway epithelia, the rate of Na+absorption and Cl- secretion and the concomitant water transport are important in determining the depth of the airway surface liquid that bathes the airway epithelia. Maintaining the optimal depth of this thin liquid layer for mucociliary clearance appears important for airway defense against pathogens. When the depth of the liquid layer is altered, as in cystic fibrosis (CF), severe disease results.

In intestinal epithelia, a balance between absorption and secretion is necessary to maintain the liquidity of intestinal contents necessary for proper digestion, enzymatic action, and mucus production. In intestine, defective regulation of secretion underlies major intestinal pathophysiology ranging from diarrhea (hypersecretion) to cystic fibrosis (hyposecretion). Control of transepithelial salt (Cl- secretion and Na+ absorption) and water transport across airway and intestinal epithelia is the major focus of my research interests.

In cystic fibrosis, a defect in the cAMP-regulated Cl- channel (CFTR) is responsible for the airway and intestinal disease phenotype exhibited by humans with the disease. With the generation of the CF mouse model in l992 (Dr. Bev Koller and colleagues), we have been able to compare and contrast the human and murine disease. We have found that with respect to airway epithelia, the disease produces a remarkably different phenotype in the human and the mouse, with the former having severe lung disease and the latter exhibiting little or no lower airway disease.
The intestinal tract of the CF mouse exhibits relatively severe pathophysiology as a result of the secretory defect. Study of intestinal ion transport in both the adult and neonatal cystic fibrosis mouse has revealed some striking similarities to the human disease. Comparison of transepithelial ion transport mechanisms in epithelia from airway and intestinal tissues (from mouse and human) has given us insight into the disparity of disease phenotypes between tissue and species.

Transport studies in my laboratory have also focused on other mouse models in which various ion transport pathways (or receptors for ligands activating these pathways) have been genetically altered (primarily in collaboration with Dr. Bev Koller). These mice are beginning to provide clues as to why alterations in certain transport pathways result in a much more severe disease phenotype than those in others.

We use a number of different techniques (both in vivo and in vitro) to study transepithelial ion and water transport across airway and intestinal epithelial cells. In vitro ion and liquid transport are studied in cultured cells by employing a planar culture system as well as a cylindrical culture system (biofiber) that re-creates the geometric configuration of airways in vivo. In vivo nasal potential difference studies are performed on the upper airways of mice, and from these measurements we can assess the ability of airway epithelia to transport Na+ and Cl-. This technique has been useful in assessing the outcome of gene transfer studies aimed at correcting the Cl- channel defect in CF mice. We have recently begun using in vivo microdialysis for the determination of airway surface liquid composition as well as the concentration of other components in the airway surface liquid. Ussing chambers are employed for studying the bioelectrics of ion transport in freshly excised neonatal and adult murine tissue.

The long-term goal of this research is to provide additional information into normal and abnormal ion and water transport physiology across epithelial cells (primarily airway and intestinal). This information will provide insight as to how transport abnormalities lead to disease phenotypes and give clues into which therapeutic interventions can be employed to overcome these ion transport defects, thus restoring normal transepithelial salt and water homeostasis.

Selected Bibliography:

  1. Donoghue LJ, Markovetz MR, Morrison CB, Chen G, McFadden KM, Sadritabrizi T, Gutay MI, Kato T, Rogers TD, Snead JY, Livraghi-Butrico A, Button B, Ehre C, Grubb BR, Hill DB, Kelada SNP. BPIFB1 loss alters airway mucus properties and diminishes mucociliary clearance. Am J Physiol Lung Cell Mol Physiol. 2023 Dec 1;325(6):L765-L775. doi: 10.1152/ajplung.00390.2022. PMID: 37847709.
  2. Yin W, Golliher HL, Ferguson AJ, Kimbell JS, Livraghi-Butrico A, Rogers TD, Grubb BR, Kimple AJ, Ostrowski LE. Mucolytic treatment of chronic rhinosinusitis in a murine model of primary ciliary dyskinesia. Front Mol Biosci. 2023 Jul 24;10:1221796. doi: 10.3389/fmolb.2023.1221796. PMID: 37555015; PMCID: PMC10405821.
  3. Mikami Y, Grubb BR, Rogers TD, Dang H, Asakura T, Kota P, Gilmore RC, Okuda K, Morton LC, Sun L, Chen G, Wykoff JA, Ehre C, Vilar J, van Heusden C, Livraghi-Butrico A, Gentzsch M, Button B, Stutts MJ, Randell SH, O’Neal WK, Boucher RC. Chronic airway epithelial hypoxia exacerbates injury in muco-obstructive lung disease through mucus hyperconcentration. Sci Transl Med. 2023 Jun 7;15(699):eabo7728. doi: 10.1126/scitranslmed.abo7728. PMID: 37285404. PMCID: PMC10664029.
  4. Grubb BR, Livraghi-Butrico A. Animal models of cystic fibrosis in the era of highly effective modulator therapies. Curr Opin Pharmacol. 2022 Jun;64:102235. doi: 10.1016/j.coph.2022.102235. PMID: 35576754. PMCID: PMC9386876.
  5. Rogers TD, Button B, Kelada SNP, Ostrowski LE, Livraghi-Butrico A, Gutay MI, Esther CR Jr, Grubb BR. Regional Differences in Mucociliary Clearance in the Upper and Lower Airways. Front Physiol. 2022 Mar 9;13:842592. doi: 10.3389/fphys.2022.842592. PMID: 35356083; PMCID: PMC8959816.
  6. Kato T, Mikami Y, Sun L, Rogers TD, Grubb BR, Morrison CB, Ehre C, Sears PR, Ostrowski LE, Randell SH, Boucher RC. Reuse of Cell Culture Inserts for in vitro Human Primary Airway Epithelial Cell Studies. Am J Respir Cell Mol Biol. 2021 Jun;64(6):760-764. doi: 10.1165/rcmb.2021-0033LE. PMID: 33788673. PMCID: PMC8456889.
  7. Okuda K, Dang H, Kobayashi Y, Carraro G, Nakano S, Chen G, Kato T, Asakura T, Gilmore RC, Morton LC, Lee RE, Mascenik T, Yin WN, Barbosa Cardenas SM, O’Neal YK, Minnick CE, Chua M, Quinney NL, Gentzsch M, Anderson CW, Ghio A, Matsui H, Nagase T, Ostrowski LE, Grubb BR, Olsen JC, Randell SH, Stripp BR, Tata PR, O’Neal WK, Boucher RC. Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia. Am J Respir Crit Care Med. 2021 May 15;203(10):1275-1289. doi: 10.1164/rccm.202008-3198OC. PMID: 33321047. PMCID: PMC8456462
  8. van Heusden C, Grubb BR, Button B, Lazarowski ER. Airway Epithelial Nucleotide Release Contributes to Mucociliary Clearance. Life (Basel). 2021 May 11;11(5):430. doi: 10.3390/life11050430. PMID: 34064654; PMCID: PMC8151306.
  9. 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.
  10. Yin W, Livraghi-Butrico A, Sears PR, Rogers TD, Burns KA, Grubb BR, Ostrowski LE. Mice with a Deletion of Rsph1 Exhibit a Low Level of Mucociliary Clearance and Develop a PCD Phenotype. Am J Respir Cell Mol Biol. 2019 Sep;61(3):312-321. doi: 10.1165/rcmb.2017-0387OC. PMID: 30896965. PMCID: PMC6839924.
  11. Bustamante-Marin XM, Yin WN, Sears PR, Werner ME, Brotslaw EJ, Mitchell BJ, Jania CM, Zeman KL, Rogers TD, Herring LE, Refabért L, Thomas L, Amselem S, Escudier E, Legendre M, Grubb BR, Knowles MR, Zariwala MA, Ostrowski LE. Lack of GAS2L2 Causes PCD by Impairing Cilia Orientation and Mucociliary Clearance. Am J Hum Genet. 2019 Feb 7;104(2):229-245. doi: 10.1016/j.ajhg.2018.12.009. PMID: 30665704. PMCID: PMC6372263.
  12. Ehre C, Rushton ZL, Wang B, Hothem LN, Morrison CB, Fontana NC, Markovetz MR, Delion MF, Kato T, Villalon D, Thelin WR, Esther CR Jr, Hill DB, Grubb BR, Livraghi-Butrico A, Donaldson SH, Boucher RC. An Improved Inhaled Mucolytic to Treat Airway Muco-Obstructive Diseases. Am J Respir Crit Care Med. 2019 Jan 15;199(2):171-180. doi: 10.1164/rccm.201802-0245OC. PMID: 30212240. PMCID: PMC6353008.
  13. Rogers TD, Ostrowski LE, Livraghi-Butrico A, Button B, Grubb BR. Mucociliary Clearance in Mice Measured by Tracking Trans-tracheal Fluorescence of Nasally Aerosolized Beads. Sci Rep. 2018 Oct 3;8(1):14744. doi: 10.1038/s41598-018-33053-2. PMID: 30282981. PMCID: PMC6170422.
  14. 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.
  15. 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.
  16. 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. PMID: 28851744. PMCID: PMC5629340.
  17. 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.
  18. Grubb BR, Livraghi-Butrico A, Rogers TD, Yin W, Button B, Ostrowski LE. Reduced mucociliary clearance in old mice is associated with a decrease in Muc5b mucin. Am J Physiol Lung Cell Mol Physiol. 2016 May 1;310(9):L860-7. doi: 10.1152/ajplung.00015.2016. PMID: 26968767. PMCID: PMC4867354.
  19. Ostrowski LE, Yin W, Patel M, Sechelski J, Rogers T, Burns K, Grubb BR, Olsen JC. Restoring ciliary function to differentiated primary ciliary dyskinesia cells with a lentiviral vector. Gene Ther. 2014 Mar;21(3):253-61. doi: 10.1038/gt.2013.79. PMID: 24451115. PMCID: PMC4124007.
  20. Roy MG, 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 JM, 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 defence. Nature. 2014 Jan 16;505(7483):412-6. doi: 10.1038/nature12807. PMID: 24317696; PMCID: PMC4001806.
  21. 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.
  22. 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.