Barbara
Grubb
Research Professor
Degrees
BS:
(1970) Ill. Wesleyan
Bloomington, IL
MS:
Northwestern U.
Chicago, IL
Ph.D.:
(1974) Northwestern U., Chicago, IL
Office:
6027 Thurston-Bowles
Phone: 919-966-5602
email:
bgrubb@med.unc.edu
Research Interests:
- Ion and water transport across epithelia (primarily airway and intestinal)
- Use of mouse models for ion transport study
- Comparative physiology (cardiopulmonary)
Alterations in transepithelial salt (and thus water) absorption and secretion result in a number 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 conentration 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 into 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.
Recent Publications:
Sloan JL, Grubb BR, Mager S.Expression of the amino acid transporter ATB 0+ in lung: possible role in luminal protein removal. Am J Physiol Lung Cell Mol Physiol. 2003 Jan;284(1):L39-49. Epub 2002 Aug 23. Click here to link to Pubmed
Grubb BR, Chadburn JL, Boucher RC. In vivo microdialysis for
determination of nasal liquid ion composition.
Am J Physiol Cell Physiol. 2002 Jun;282(6):C1423-31. Click
here to link to Pubmed
Grubb BR. Bioelectric measurement of CFTR function in mice. Methods Mol Med. 2002;70:525-35. Click here to link to Pubmed
Caldwell RA, Grubb BR, Tarran R, Boucher RC, Knowles MR, Barker PM.In vivo airway surface liquid Cl- analysis with solid-state electrodes. J Gen Physiol. 2002 Jan;119(1):3-14. Click here to link to Pubmed
Randell SH, Walstad L, Schwab UE, Grubb BR, Yankaskas JR. Isolation and culture of airway epithelial cells from chronically infected human lungs.In Vitro Cell Dev Biol Anim. 2001 Sep;37(8):480-9. Click here to link to Pubmed
Tarran R, Grubb BR, Parsons D, Picher M, Hirsh AJ, Davis CW, Boucher RC. The CF salt controversy: in vivo observations and therapeutic approaches. Mol Cell. 2001 Jul;8(1):149-58. Click here to link to Pubmed
Tarran R, Grubb BR, Gatzy JT, Davis CW, Boucher RC. The relative roles of passive surface forces and active ion transport in the modulation of airway surface liquid volume and composition. J Gen Physiol. 2001 Aug;118(2):223-36. Click here to link to Pubmed
Grubb BR, Pace AJ, Lee E, Koller BH, Boucher RC. Alterations in
airway ion transport in NKCC1-deficient mice.
Am J Physiol Cell Physiol. 2001 Aug;281(2):C615-23. Click
here to link to Pubmed
Lazarowski ER, Rochelle LG, O'Neal WK, Ribeiro CM, Grubb BR, Zhang V, Harden TK, Boucher RC.Cloning and functional characterization of two murine uridine nucleotide receptors reveal a potential target for correcting ion transport deficiency in cystic fibrosis gallbladder. J Pharmacol Exp Ther. 2001 Apr;297(1):43-9. Click here to link to Pubmed
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