The candidate, Dr. Stark, received a B.S. in Biology from the Cleveland State University, and his Ph.D and M.D. degrees from Case Western Reserve University through the Medical Scientists Training Program. His Ph.D. Thesis described plasmid-encoded hemolysin of E. coli. Dr. Stark received clinical training in Pediatrics, and subspecialty training in Pediatric Pulmonology. The research project during his fellowship training focused on the description of the molecular biology of Parainfluenza virus type 2, and on establishing an in vitro model for viral lower respiratory tract infection. Dr. Stark joined the faculty at the University of Wisconsin in July l989 as an Assistant Professor (tenure track) in the Department of Pediatrics. In association with Dr. Busse, he has obtained the preliminary data presented and developed the proposed project. The hypothesis for the proposed project is that viral infection of the lower airway causes the expression of new or altered surface molecules (proteins) on the airway epithelium which are recognized by inflammatory cells, resulting in the """"""""priming"""""""" or activation of these cells. The expression of these antigens is, therefore, the pivotal step in subsequent airway injury and airway smooth muscle hyperreactivity. This hypothesis is supported by preliminary studies presented here that demonstrate neutrophil and eosinophil recognition of infected airway epithelium. The research project focuses on the interactions between viral glycoproteins expressed on human airway epithelial cells and airway inflammatory cells (neutrophils and eosinophils). The genes for the glycoproteins will be cloned into an expression vector and transfected into an immortalized epithelial cell line. The following measures of cellular interactions will be studied: 1) attachment; 2) cell activation, mediator production, and mediator release; 3) target cell killing. In summary, these studies will use the infection model to investigate the interaction of infected airway epithelial cells with neutrophils and eosinophils and determine the relationship of this interaction to the epithelial pathology. The Department of Pediatrics and Medicine at the University of Wisconsin have longstanding commitments to research. The candidate's sponsor, Dr. William Busse (Professor and Head of the Allergy and Clinical Immunology Section at the UW-Madison), has a longstanding interest and recognized expertise in asthma and the eosinophil, and has several NIH grants dealing with the viral infections and asthma. The candidate's co-sponsor, Dr. Philip Farrell (Chairman of the Department of Pediatrics), has a strong background in basic science research and a long-term commitment to establishing research programs in this department. The candidate is assured protected time and facilities for the proposed project.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL002505-01A1
Application #
3082933
Study Section
Research Manpower Review Committee (MR)
Project Start
1991-09-01
Project End
1996-08-31
Budget Start
1991-09-01
Budget End
1992-08-31
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Wilmott, R W; Kitzmiller, J A; Fiedler, M A et al. (1998) Generation of a transgenic mouse with lung-specific overexpression of the human interleukin-1 receptor antagonist protein. Am J Respir Cell Mol Biol 18:429-34
Chini, B A; Fiedler, M A; Milligan, L et al. (1998) Essential roles of NF-kappaB and C/EBP in the regulation of intercellular adhesion molecule-1 after respiratory syncytial virus infection of human respiratory epithelial cell cultures. J Virol 72:1623-6
Stark, J M; Godding, V; Sedgwick, J B et al. (1996) Respiratory syncytial virus infection enhances neutrophil and eosinophil adhesion to cultured respiratory epithelial cells. Roles of CD18 and intercellular adhesion molecule-1. J Immunol 156:4774-82
Stark, J M; Amin, R S; Trapnell, B C (1996) Infection of A549 cells with a recombinant adenovirus vector induces ICAM-1 expression and increased CD-18-dependent adhesion of activated neutrophils. Hum Gene Ther 7:1669-81
Godding, V; Stark, J M; Sedgwick, J B et al. (1995) Adhesion of activated eosinophils to respiratory epithelial cells is enhanced by tumor necrosis factor-alpha and interleukin-1 beta. Am J Respir Cell Mol Biol 13:555-62
Fiedler, M A; Wernke-Dollries, K; Stark, J M (1995) Respiratory syncytial virus increases IL-8 gene expression and protein release in A549 cells. Am J Physiol 269:L865-72
Stark, J M; van Egmond, A W; Zimmerman, J J et al. (1992) Detection of enhanced neutrophil adhesion to parainfluenza-infected airway epithelial cells using a modified myeloperoxidase assay in a microtiter format. J Virol Methods 40:225-42