Scott Donaldson
Assistant Professor of Medicine
Degrees
BS:
(1986) U. of Michigan, Ann Arbor, MI
MD:
(1990) U. of Michigan, Ann Arbor, MI
Residency:
(1990-93)
Dartmouth, Hanover, NH
Fellowship:
(1993-98)
UNC, Chapel Hill, NC
Office:
6019 Thurston-Bowles
Phone: 919-966-9198
Fax: 919-966-7524
email:
scott_donaldson@med.unc.edu
Research Interests:
The lung is protected against inhaled organisms and particles by mucociliary clearance. Inhaled particles bind to a secreted mucus layer, which rests on top of a thin film of fluid. The volume/height of this thin fluid layer is tightly regulated so that coordinated ciliary beating efficiently propels this mucus blanket toward the proximal airways. A key determinant of airway surface liquid volume is the rate of sodium absorption through the epithelial sodium channel (ENaC). In cystic fibrosis (CF) sodium absorption is excessive, leading to a depleted airway surface liquid layer, poor mucociliary clearance, and subsequent chronic infection. Research in this lab is directed at understanding the processes that regulate ion transport and mucociliary clearance, in an attempt to develop therapies aimed at correcting the underlying defects present in CF lung disease.One focus of this lab is the regulation of the ENaC, which forms the rate-limiting step in fluid absorption from the lung. Using the xenopus oocyte expression system, the impact of genes encoding candidate proteins on whole cell ENaC currents and single channel kinetics are tested. These results are then used to guide experiments using various epithelial cell models. Ultimately, the goal of this research is to modify ion transport in vivo in a way that improves mucociliary clearance.
A second avenue being explored as a means to alter ion transport in vivo, and thereby enhance mucociliary clearance, is the use of nucleotide receptor agonists. Activation of the dominant airway nucleotide receptor, P2Y2, leads to secretion of chloride/water via non-CFTR chloride channels, mucin secretion via goblet cells, and more rapid ciliary beating. This triad of effects combines to increase mucociliary clearance in normal subjects, as well as in patients with CF. A potential shortcoming of this therapy is the presence of enzymes that hydrolyze typical P2Y2 agonists (e.g. ATP, UTP), thus dramatically decreasing their half-life. Our lab, therefore, is characterizing cell surface and secreted enzymes that may impact the profile of endogenous/exogenous nucleotides in airways, so that therapeutic rational approaches aimed at targeting these receptors may be devised.
Recent Publications:
Donaldson SH and Boucher, RC. Update on pathogenesis of cystic fibrosis lung disease. Curr Opin Pulm Med. 2003;9(6):486-491. Click here to link to Pubmed
Donaldson SH, Poligone EG, Stutts MJ. CFTR regulation of ENaC. Methods Mol Med. 2002;70:343-64. Click here to link to Pubmed
Donaldson SH, Picher
P, Boucher RC. Cell surface and secreted adenylate kinase and nucleoside
diphosphokinase contribute to extracellular nucleotide metabolism in airways.
Am J Respir Cell Mol Biol. 2002 Feb;26(2):209-15. Click
here to link to Pubmed
Donaldson SH, Hirsh
A, Li DC, Holloway G, Chao J, Boucher RC, Gabriel SE. Regulation of the
Epithelial Sodium Channel by Serine Proteases in Human Airways. J Biol
Chem 2002;277(10):8338-45. Click
here to link to Pubmed
Donaldson SH, Lazarowski
ER, Picher M, Knowles MR, Stutts MJ, and Boucher, RC. Basal Nucleotide
Levels, Release, and Metabolism in Normal and Cystic Fibrosis Airways.
Molecular Medicine. 2000: 6(11):969-982. Click
here to link to Pubmed
Abstracts:
Donaldson SH, Bennett W, Zeman K, Knowles MR, Boucher RC. Efficacy of Amiloride and Hypertonic Saline in Cystic Fibrosis Ped. Pulm Supp. 25. 2003: A194.
Lazarowski ER, Grubb B, Donaldson
S, van Heusden CA, Boucher RC. Extracellular Adenyl Purines Provide
a Mechanism of Control for A2B Receptor-Mediated Epithelial Cell Responses.
Ped. Pulm. 2002: A163.
Donaldson SH, Gilmore
ES, Milgram SL, Stutts MJ. Regulation of the epithelial sodium channel
by Src-family kinases. Ped. Pulm. 2000: A112.
Mohler PJ, Donaldson SH,
Kreda SK, Boucher RC, Stutts MJ, Milgram SL.Yes-associated protein 65
localizes P62C-Yes to the apical compartment of airway epithelia by association
with EBP50. Ped. Pulm. 1999: 19:A293.
Donaldson SH, Holloway
G, Li DC, Chao J, Boucher RC, Gabriel SE: Serine protease regulation of
the epithelial sodium channel (ENaC). Ped. Pulm. 1998
Milgram SL, Kreda S, Donaldson
S, Short B, Kultgen P, Winders A, Boucher RC, Stutts MJ: The COOH-terminus
of CFTR associates with the apical cytoskeleton via a PDZ domain in EBP50.
Ped. Pulm. 1998
Donaldson SH, Stutts
MJ, Boucher RC, Knowles MR: In vivo regulation of ATP levels in human
nasal epithelia. Ped. Pulm. 1996;13:289.
Donaldson SH, Stutts
MJ, Boucher RC, Knowles MR: Adenosine triphosphate levels in nasal surface
liquid. Am. J. Resp. Crit. Care Med. 1996;153(4):A854.
Pinto-Powell R, Donaldson S, Olivier K, Parker, HW, Boyle W, Hohneker K, Knowles MR, von Reyn CF: Dual skin testing and sputum cultures to identify infection with Mycobacterium avium complex in patients with cystic fibrosis. Ped. Pulm. 1994;10:257.
Book Chapters:
Donaldson SH, Yankaskas
J: Cystic Fibrosis, in Hess D, MacIntyre N, Mishoe SC, Galvin WF, Saposnick
AB, Adams A (eds): Respiratory Care: Principles and Practice. Orlando,
FL, W.B. Saunders Company; 2002:1003-1021.
Donaldson SH, Boucher
RC: Therapeutic Applications for Nucleotides in Lung Disease, in Turner
J, Weisman G, and Fedan J (eds): The P2 Nucleotide Receptors. Totowa,
NJ, The Humana Press Inc.; 1998:413-424.
Erickson RP, Bevilacqua A,
Ross C, Donaldson S, Stalvey JRD: Do BKM sequences play a role
in human sex determination? In Haseltine FP, McClure ME, and Goldberg
EH (eds): Genetic Markers of Sex Differentiation. New York, NY,
Plenum Publishing Corporation; 1987:149-159.
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