Scott H Donaldson, MD

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Research Focus

Donaldson
Scott H Donaldson, MD, Associate Professor of Medicine

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 in CF lung disease.

One focus of this lab is the regulation of the ENaC, which is the rate-limiting step in fluid absorption from the lung. We use the Xenopus oocyte expression system to test   the impact of genes encoding candidate proteins on whole cell ENaC currents and single channel kinetics. The 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 causes cilia to beat more rapidly. 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.

DonaldsonA

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Biographical Sketch

Education and Training

B.S. – Biology, University of Michigan, Ann Arbor, Michigan, 1986.

M.D., University of Michigan, Ann Arbor, Michigan, 1990.

Medical Internship and Residency, Dartmouth-Hitchcock Medical Center, Hanover, New Hampshire, 1990-1993.

Pulmonary and Critical Care Fellowship, University of North Carolina, Chapel Hill, North Carolina, 1993-1998.

Professional Experience

Research Assistant Professor, Department of Medicine, Division of Pulmonary/Critical Care Medicine, University of North Carolina at Chapel Hill, 1998-2003.

Assistant Professor, Department of Medicine, Division of Pulmonary/Critical Care Medicine, 2003-2009.

Associate Professor, Department of Medicine, Division of Pulmonary/Critical Care Medicine, 2009 - present.

Associate Director, UNC Adult Cystic Fibrosis Program, 2006 – present.

Grants Funded and Research Contracts

  • “Detection of CFTR in Rectal Tissues from Human Subjects (ICM001)"
    -Cystic Fibrosis Foundation Therapeutics, Inc., Clinical Research Grant
    -Funded 11/1/2009 – 10/31/2010 (site P.I.)

  • “A Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose Study of VX-809 to Evaluate Safety, Pharmacokinetics, and Pharmacodynamics of VX-809 in Cystic Fibrosis Subjects Homozygous for the Δ F508-CFTR Gene Mutation”
    -Vertex Pharmaceuticals, Inc.
    -Funded 3/10/09 – 3/09/12 (site P.I.)

  • “A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of VX-770 in Subjects with Cystic Fibrosis and the G551D Mutation”
    -Vertex Pharmaceuticals, Inc.
    -Funded 6/29/09 – 6/28/12 (site P.I.)

  • “A Phase 2, Double-Blind, Multicenter, Randomized, Placebo-Controlled Trial Evaluating Fosfomycin/Tobramycin for Inhalation in Patients with Cystic Fibrosis and Pseudomonas aeruginosa (GS-US-207-0103)”
    -Gilead Sciences, Inc.
    -Funded 2/3/09 – 2/2/12 (site P.I.)

  • “Durability of Hypertonic Saline for Enhancing Mucociliary Clearance in Cystic Fibrosis
    -Novartis Pharmaceuticals Corp.
    -Funded 6/1/09 – 5/31/10 (co-I.)

  • “A Phase 3 Efficacy and Safety Study of PTC124 as an Oral Treatment for Nonsense-Mutation-Mediated Cystic Fibrosis
    -PTC Therapeutics, Inc.
    -Funded 11/1/09 – 10/31/11 (site co-I.)

  • “Idealized Care of Pulmonary Exacerbations”
    -Cystic Fibrosis Foundation, Clinical Research Grant
    -Funded 1/1/09 – 12/31/10 (P.I.)

  • “CF Therapeutic Development Center”
    -Cystic Fibrosis Foundation Therapeutics, Inc.
    Funded 1/1/2009 – 12/31/2010 (co-P.I.)

  • “In vivo measurement of small airway mucociliary clearance”
    -Cystic Fibrosis Foundation, Clinical Research Grant
    -Funded 1/1/08 – 12/31/10 (P.I.)

  • A Randomized, Double-Blind, Two Way Crossover Evaluation of the Effects of a Single Dose of Denufosol Tetrasodium (INS37217) Inhalation Solution versus Placebo (0.9% sodium chloride solution) on Mucociliary Clearance in Patients with Mild to Moderate Cystic Fibrosis Lung Disease.
    -Inspire Pharmaceuticals
    -Funded 7/26/07 – 7/25/08 (P.I.)

  • “A Phase 2a, Randomized, Double Blind, Placebo-Controlled Study of VX-770 to Evaluate Safety, Pharmacokinetics, and Biomarkers of CFTR Activity in Cystic Fibrosis (CF) Subjects with genotype G551D”.
    -Vertex Pharmaceuticals Inc.
    -2/15/2007 – 4/11/2010 (site P.I.)

  • “SCCOR in Host Factors in Chronic Lung Disease”
    -NIH/NHLBI (Overall P.I.: R. C. Boucher)
    -Funded 9/15/06 – 7/31/11 (P.I. Project VI)

  • “Mucus Clearance During Exacerbations of Cystic Fibrosis Lung Disease”
    -Cystic Fibrosis Foundation, Clinical Research Grant
    -Funded 1/1/06-12/31/10 (P.I.)

  • “Standardization of Mucociliary Clearance Methodology”
    -Cystic Fibrosis Foundation, Clinical Research Grant
    -Funded 1/1/06 – 12/31/08 (co-I)

  • “Efficacy of Aerosolized Surfactant +/- Hypertonic Saline for Cystic Fibrosis Lung Disease”
    -Cystic Fibrosis Foundation, Clinical Research Grant
    -Funded 4/1/05-3/31/10 (P.I.)

  • “The Effect of Treatment with a Single Aerosolized Dose of 552-02 on Normal Healthy Volunteers”
    -Parion Sciences, Inc.
    -Funded 9/15/04 – 9/14/05 (P.I.)

  • “Validity of a Novel Device to Assess Cardiorespiratory Function in Cystic Fibrosis”
    -Cystic Fibrosis Foundation, Clinical Research Grant
    -Funded July 1, 2003 – June 30, 2004 (P.I.)

  • “Failure of Anti-Protease Regulation of ENaC in CF”
    -CF Foundation RDP Grant (Project P.I.; Overall P.I., R. Boucher)
    -Funded 7/01/03 – 6/30/04 (Project 4 P.I.)

  • “A Phase IIa, Safety and Efficacy Study of Oral SPI-8811 in Patients with Cystic Fibrosis”
    -Sucampo Pharmaceuticals, Inc. 
    -Funded 3/4/2003 – 3/3/2004 (site P.I.)

  • “Comprehensive Analysis of Malnutrition in Adults with Cystic Fibrosis”
    -UNC Clinical Nutrition Research Center and GCRC
    -Funded September 30, 2002 – September 29, 2004 (P.I.)

  • “Regulation of ENaC by Serine Proteases in Airways
    -NIH/NHLBI (K08)
    -Funded May 16, 2002 – April 30, 2007 (P.I.)

  • “Efficacy of Amiloride and Hypertonic Saline in Cystic Fibrosis”
    -Cystic Fibrosis Foundation, Clinical Research Grant
    -Funded July 1, 2000 – June 30, 2002 (P.I.)

  • “Regulation of the ENaC by Serine Proteases in Airways” (P.I. Project 18)
    -CF Foundation RRDP Grant (Overall PI: R. Boucher)
    -Funded March 1, 2001– February 28, 2002

Special Honors and Awards

  • Leroy Matthews Physician-Scientist Award
    -Cystic Fibrosis Foundation
    -Funded salary/research July 1, 1995 – June 30, 2001
  • Allen & Hanburys Respiratory Institute
    -1995 Pulmonary Fellowship Award (funded salary for 1 year)
    -Research topic: “Regulation of purinergic receptors in airways”

Other Activities

UNC, Cystic Fibrosis Center, and Pulmonary Division:

  • Led development of the interdisciplinary UNC Adult Cystic Fibrosis Clinic (commenced 7/9/98).
  • Associate Director of Adult CF Center 2006-present.
  • UNC Therapeutic Development Center (Co-PI).
  • Site PI or co-Investigator for multiple, multicenter clinical trials of CF therapies through the CF Therapeutic Development Network (2002-present).
  • UNC Data Warehouse Operations Committee (2/14/2008 – present).

National Cystic Fibrosis Research Activities

  • Patient Advocacy and Ethics Committee; CF Therapeutic Development Network (2003-2005).
  • Protocol Review Committee; CF Therapeutic Development Network (2005-present).
  • Translational Center Committee (2009 – present); Vice Chair 2009-present. Assumes Chair 1/2011.
  • CF Foundation Clinical Research Committee (2006-present).
  • Mucociliary Clearance Working Group, Chair; CF Therapeutic Development Network (2006-present).
  • UNC Cystic Fibrosis QI Lead Team (6/04 – present).
  • National CF QI Consortium: Learning and Leadership Collaborative II (6/04 – 6/05).
  • QI Coach for CF Center QI Teams within national “Learning and Leadership Collaborative” LLC III (Johns Hopkins University) (2005).

LLC IV (Indiana University) (2006-07).

LLC V (Rochester University and Case Western University) (2007-08).

LLC VI (Yale University and Children’s Hospital of the King’s Daughter) (2008-present).

  • QI Faculty, LLC V

Publications

Please see Pubmed feed in the righthand column for links to current publications.

Presentations

Invited Symposia and Presentations

“What is in the CF Lung before Pulmonary Symptoms?” European CF Symposia. Valencia, Spain. June 16, 2010.
“Pathogenesis of Cystic Fibrosis”. American Thoracic Society. New Orleans, LA. May 18, 2010.
“Pathogenesis of Cystic Fibrosis”. International Society of Aerosol Medicine. Monterey, CA. May 11, 2009.
“Bronchiectasis and Adult Cystic Fibrosis: Diagnosis and Management”. Challenges in Pulmonary and Critical Care: 2008. Cleveland Clinic, Weston, FL. November 15, 2008.
“Longitudinal Assessment of Mucociliary Clearance in CF: Repeatability and Impact of Exacerbations”. Workshop: Airway Defense: Mechanisms & Outcome Measures. North American CF Conference; Orlando, FL. October 2008.
“Hydration Therapies to Improve Mucociliary Clearance” International Society of Aerosol Medicine Symposium: Mucociliary/Cough Clearance as a Biomarker for Therapeutic Development. Research Triangle Park, NC. October 21, 2008.
“Mucociliary Clearance: A target for treatment in CF and COPD”. Respiratory Drug Development 2008. Scottsdale AZ. May 12, 2008.
“Measuring and Modulating Mucociliary Clearance in CF”. Duke University Airway Biology Seminar. Durham, NC. March 28, 2008.
“Hypertonic Saline for CF Lung Disease”. Plenary Lecture, Spain’s Cystic Fibrosis Conference. Madrid, Spain. March 7, 2008.
“Measures of Mucociliary Clearance in Assessment of New CF Therapies”. Symposia: Outcome Measures to Assess CF Interventions. North American CF Conference; Anaheim, CA. October 2007.
“Hypertonic Saline and ENaC Inhibitors for CF Lung Disease”. Symposia: New and Emerging Therapies for Cystic Fibrosis. American Thoracic Society; San Francisco, CA; May 2007.
“Role of Airway Surface Hydrators for CF Lung Disease”. Symposia: Aerosol Therapies in Cystic Fibrosis. North American CF Conference; Denver, CO. November 3, 2006.
“Hypertonic Saline is the Preferred Therapy for Augmentation of Airway Clearance”. Symposia: Pulmonary Controversies – An International Perspective. North American CF Conference; Denver, CO. November 5, 2006.
Hypertonic Saline for Cystic Fibrosis Lung Disease”. Duke University Medical Center; Pediatric Pulmonary/CF Research Conference. December 2005.
“A Pilot Study of Amiloride and Hypertonic Saline in Cystic Fibrosis”. North American Cystic Fibrosis Conference; St. Louis, MO. October, 2004.
“A Pilot Study of Amiloride and Hypertonic Saline in Cystic Fibrosis”. CFF Williamsburg Conference. Williamsburg, VA. June 2004.
“Protease Regulation of ENaC”. Case Western Reserve University, Pediatric Pulmonary Research Seminar; Cleveland, OH; December 2003.
“Localized Apical Regulation of Airway Epithelial Ion Transport.” American Thoracic Society; Atlanta, GA; April 2002.
“Clinical Microbiologic and Infection Control Considerations in Cystic Fibrosis.” Southeast CF Caregivers Conference; Chapel Hill, NC; March 1999.
“Modulators of Ion Transport.” International Congress for the Society of Aerosol Medicine; Rome, Italy; December 1998.
“Therapies on the horizon for cystic fibrosis lung disease.” American Society of Health-System Pharmacists; Baltimore, MD; June 1998.
“Cystic fibrosis presenting as chronic pancreatitis and congenital absence of the vas deferens.” North American Cystic Fibrosis Conference; Dallas, TX; October 1995. (Session moderator)
“Abdominal granulomatous disease in cystic fibrosis.” North American Cystic Fibrosis Conference; Orlando, FL; October 1994.

UNC Departmental Conferences

1. UNC Epithelial Biology Seminar (March 19, 2010): “Pathogenesis of Cystic Fibrosis Exacerbations.”
2. UNC Pulmonary didactic Lecture Series (September 25, 2009): “Fungal Diseases of the Chest.”
3. UNC Pulmonary didactic Lecture Series (July 24, 2009): “Introduction to CF.”
4. UNC UNC Internal Medicine Residents Lecture (September 16, 2008): “Cystic Fibrosis, State of the Art.”
5. UNC Internal Medicine Residents Lecture (August 4, 2008): Pulmonary Function Testing6. UNC Pulmonary Didactic Lecture Series (December 18, 2007): “Fungal Pulmonary Infections.”
7. UNC Pulmonary Medicine Research Conference (December 7, 2007): “Mucus Dehydration and Evolution of CF Lung Disease.”
8. UNC Internal Medicine Residents Lecture (Nobember 6, 2007): “Cystic Fibrosis, State of the Art.”
9. UNC Pulmonary Didactic Lecture Series (September 25, 2007): “Cystic Fibrosis.”
10. UNC Pulmonary Didactic Lecture Series (July 11, 2006): “Quality Improvement.”
11. UNC Pulmonary Didactic Lecture Series (February 28, 2006): “Cystic Fibrosis, State of the Art.”
12. UNC Internal Medicine Residents Lecture (November 22, 2005): “CF Therapies.”
13. UNC Pulmonary Didactic Lecture Series (January 18, 2005): “Quality Improvement.”
14. UNC Pediatric Pulmonary Medicine (November 1, 2004): “Hypertonic Saline for CF Lung Disease.”
15. UNC Pulmonary Didactic Lecture Series (October 12, 2004): “Hypertonic Saline for CF Lung Disease.”
16. UNC Department of Nutrition (May 2004) “Clinical Assessment of Malnutrition in Cystic Fibrosis.”
17. UNC Internal Medicine Residents Lecture (December 8, 2003): Cystic Fibrosis Review.
18. UNC Internal Medicine Residents Lecture (March 4, 2002): CF State of the Art.
19. UNC Epithelial Biology Seminar (April, 1999): “Xenopus oocytes and ENaC Regulation.”
20. UNC Department of Medicine CPC: (September, 1996): “Pulmonary infiltrates in a patient with dermatomyositis.”

Continuing Education Lectures

1. “Evidence Based Care of COPD”. Moses Cone Hospitals Grand Rounds. February 12, 2010.
2. “Improving Outcomes in COPD”. Wake Med Grand Rounds. September 23, 2008.
3. “Improving Outcomes in the COPD Patient”. Nash Hospital. December 19, 2007.
4. “COPD State of the Art”. Family Medicine Conference. New Hanover RMC. October 27, 2006.
5. “Pulmonary Function Testing”. Caswell Family Medicine. August 2005.
6. “Update on COPD”. Westcare. March 2005.
7. Wake Med Grand Rounds (May 2004): “COPD – What’s New and What Works.”
8. “COPD: What’s New and What Works”. Dorothy Dix. May 2004.
9. “Asthma: Assessment and Treatment in Primary Care”. NC State Student Health Department. December 2002.

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Contact Information

6007b Thurston-Bowles Bldg.
The University of North Carolina at Chapel Hill
Campus Box # 7248
Chapel Hill, NC 27599
Phone: (919) 966-9198
Fax: (919) 966-5178
Email:
scott_donaldson@med.unc.edu

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