- The Biophysics and Biochemistry of large complex glycoconjugates with special reference to mucins and proteoglycans in the human lung.
- The dynamics of cilia mucus interactions in the lung.
- The dynamics of biomolecule-water interactions as studied by molecular dynamics methods.
The focus of my current work may be brought down to the question of the basic mechanisms of innate immunity in the lung. The upper airway is protected by two complex interacting gel systems, one surrounding the cilia and the other attached above. These two complex layers are structured by large complex molecules called mucins. These molecules form the scaffold onto which are attached some two hundred other molecules (globular proteins) most of which have known or suspected functions concerned with innate immunity (i.e. recognition and interaction with chemical, physical and pathological irritants). This system acts as an integrated whole and in diseases such as chronic bronchitis, asthma, cystic fibrosis and many other diseases it fails. In cystic fibrosis (my main interest), we know exactly the source of the failure (the gene defect) but be we do not know the direct impact of the defect onto the local protective gels mentioned above. My recent data suggest that in CF, the primary defect itself is having a profound effect on the mucin structure at or around the time of their secretion. This knocks on to the whole gel network and compromises the system and its protective functions especially with regard to bacteria. These data make direct predictions as to possible remedial physical and therapeutic action to be taken to alleviate the primary cause of sickness and death in this disease.
John K Sheehan, PhD, Hooker Professor of Biochemistry and Physics
(1965-1968) B.Sc. Physics Leicester University.
(1969-M.Sc. Materials Science Bristol University.
(1970-1973) Ph. D. Biophysics Bristol University.
(2002-present) Michael Hooker Prof. of Biophysics and Biochemistry, UNC- Chapel Hill.
(1998-2002) Reader in Biochemistry, Manchester University.
(1986-1998) Wellcome Senior Lecturer, Manchester University.
(1982-1985) Cystic Fibrosis Research Fellow, Lancaster University.
(1980-1982) MRC(Swedish) Visiting Scientist at Lund University.
(1979) Visiting Scientist, Purdue University (with Prof. Struther Arnott).
(1973-1979) MRC Postdoctoral Fellow, Bristol and Lancaster University.
(1995-1999) Biochemical Society: Chairman of the Glycobiology Group.
1-P50-HL084934-01 (Sheehan) 9/15/06-7/31/11 NIH/NHLBI $247,265
Subacct: Core C Mucus Analysis-SCCOR in Host Factors in Chronic Lung Disease
The major goal of this proposal will offer to each basic science and clinical project in the SCCOR extensive services characterizing mucus samples with respect to its biochemical composition and biophysical properties including Mucus Hydration, Mucus Biophysics, and Mucin Biochemistry.
1-P50-HL084934-01 (Sheehan) 9/15/06-7/31/11 NIH/NHLBI $326,123
Subacct: Proj 1 Mucus Transport-SCCOR in Host Factors in Chronic Lung Diseases
The major of this proposal is for the structure and function of the protective mucus barrier in the large airways. We will use human bronchial epithelial cell line and normal and pathological sputum to characterize the properties of the PGL and to identify the molecular mechanisms underlying the MUC5Ac-rich gel and the MUC5B flowing mucus.
Michael Hooker Chair in Proteomics
Bequest $1.6 million to establish proteomics unit in CF Center
5 R01 EB 00761-03 (Superfine) 9/30/02-8/31/07 NIH/NIBIB $300,609
3D Force Microscopy for Microrheology and Active Transport
The major goal of this proposal is to develop magnetic bead manipulation into a new microscopic technology for studying forces and rheology in biological systems.
5 P50 HL 60280-07 (Boucher) 9/1/03-8/31/08 NIH/NHLBI $262,994 (sub only)
SCOR in Airway Biology/Pathogenesis of Cystic Fibrosis, Project III: The Biology of Mucus and Mucus Plaques on CF Airways
The major goal of this project is to evaluate the behavior of mucins secreted into a volume depleted CF airway surface environment.
1 R01 HL077546-01A1 (Superfine) 7/1/06-6/30/11 NIH/NHLBI $1,268,882
The Virtual Lung: Integrated Modeling of Epithelial Fluid Flows
The major goal of this project is to study mucociliary clearance from the consequences of genetic mutations and biochemical networks up to the scale of macroscopic hydrodynamics and to develop an integrated computational model that will be able to predict and evaluate effective therapeutic strategies for diseases of the lung.
R01 RFA HL-04-036 (Boucher) 9/30/05-9/29/10 NIH/NHLBI $275,000
Mucus Clearance in Acute COPD Exacerbations
The major goal of this project is to test the hypotheses that (1) a COPD acute exacerbation (AE) reflects a transient worsening/failure of a major human airway defense system (the mucus clearance mechanism) (2) the COPD patient is vulnerable to triggers of AEs because mucus clearance is chronically compromised by cigarette smoke-induced inflammation/damage, and (3) respiratory viruses trigger many COPD AEs via direct infection of the lower airway epithelium and derange the epithelial ion transport regulatory systems that coordinate sal/water transport and mucin secretion rates.
Grants Funded in UK 1987 - 2001
Mucus glycoproteins: an ancient barrier under new attack. (Programme grant) £300K (Wellcome Trust) 87-91.
Respiratory Mucins: structure, macromolecular properties and cellular origin. £70K (CF Trust) 87-90.
Quantitation of blot profiles by image analysis techniques. £10K (Wellcome Trust) 90-9. A study of the molecular biology of human mucin core proteins. £27K (Wellcome Trust) 90-91.
Fingerprinting respiratory mucin oligosaccharides. £45K (British Lung Found.) 92-94. Mucus glycoproteins: an old barrier under new attack. (Programme grant) £450K (Wellcome Trust) 92-96.
Size and form in assemblies of matrix molecules. £75K (Wellcome Trust) 91-93. Establishment of Wellcome Trust Centre for Cell-Matrix Research £2,220K (Wellcome Trust) 95-01.
Mucins: a strategic defence barrier. (Programme Grant) £447K (Wellcome Trust) 97-02.
Are mucins altered in asthma? £80K (Natl. Asthma Camp.) 97-00.
Equipment grant. £60K (Wellcome Trust/) 97.
Small protein proteomics. £40K (Wellcome Trust) 97.
Molecular Dynamics Approaches to Glycosaminoglycans. £55K (Wellcome Trust) 97-00.
Small protein proteomics. (renewal) £150K (Wellcome Trust) 99-01.
Structural and functional domains of a cartilage proteoglycan. £114K (Arthritis & Rheum.) 99-02.
The Molecular Basis of Mucus Gels. £168K (Wellcome Trust) 99-02.
Models to study self and non-self recognition at the cell level. £68K (Wellcome Trust) 99-01.
Studies on the basis of mucin intracellular packing and assembly. £70K (Wellcome Trust) 99-01.
As Wellcome Senior Lecturer and Reader 1986-2002 I organized, taught and examined numerous courses both practical and theoretical in the Dept. of Biological Sciences in the University of Manchester at every level from Medical Students, to Undergraduate to Post Graduate. In the UK system there is much more direct contact of staff with undergraduate students. I ran a tutoring system in which I taught groups of 5-9 students throughout two semesters on most years. We also have year long laboratory project based undergraduate work in the final undergraduate year.
3rd year special biochemists (20-35 students)
Glycobiology: the role and importance of complex carbohydrate-protein molecules in biology and medicine: 20 lectures, organizer, lecturer (10), examiner
The Physical Biochemistry of very large Macromolecules (3rd year)
Lecturer (10 lectures)
Modern Mass Spectrometry Methods in Biochemistry
Electron Microscopy Methods for large macromolecules
The Ph.D students I have trained and brought through my laboratory are listed below
Supervision of research students at Manchester University, UK:
Student Funding body Ph.D.
Helen Young (1991-1994) MRC Awarded (1995)
Ravi Mehrotra (1994-98) BBSRC Awarded (1997)
Saduman Kutay (1993-97) Turkish Govt. Awarded (1997)
Chris Tselepis (1994-98) ARC Awarded (1998)
Nurten Aksoy (1995-98) Turkish Govt. Awarded (1998)
Andrew Almond (1995-98) Wellcome Prize Awarded (1998)
Tony Reardon (1994-99) Charity Awarded (1999)
Nagma Khan (1997-99) Case student Awarded (1999)
Mary Millichip(1996-01) Guide Dogs Charity Awarded (2001)
David Knight (1998-02) Industrial sponsor Awarded (2001)
Simon Balance (1996-01) BBSRC Awarded (2001)
Linda Eyers (2000-01) BBSRC Awarded (2003)
Mathew Wakefield (1999-03) Wellcome Prize Awarded (2003)
Bertrand Raynal (1999-03) Self Finance Awarded (2003)
Please see Pubmed feed in the righthand column for links to current publications.
|John K Sheehan, PhD, Hooker Professor of Biochemistry & Physics||Mehmet Kesimer, PhD, Research Assistant Professor of Biochemistry & Physics||Patrick Sears, PhD, Research Associate|
The University of North Carolina at Chapel Hill
Campus Box #7248
Chapel Hill, NC 27599
Phone: (919) 843-2577