The bronchiolar epithelium is an important first line of defense against inhaled environmental stimuli, including microbial products such as CpGcontaining unmethylated DNA. The hypothesis to be tested in this proposal is whether CpG DNA induces signal transduction culminating in activation of the transcription factor NF-kappaB. It is proposed that the pattern recognition receptor (PRR) Toll Like Receptor (TLR)9 is expressed by bronchiolar epithelial cells and initiates signaling induced by CpG DNA. It will be examined whether expression and activity of the NF-kappaB-regulated polymeric immunoglobulin receptor (pIR), essential for the transport of IgA and IgM from the basal to the apical surface of bronchiolar epithelial cells, is augmented by CpG DNA. Finally, the modulation of these pathways in bronchiolar epithelium by CpG DNA may be therapeutically exploited to afford mucosal protection through the augmentation of secretary immunoglobulin levels. The hypothesis will be tested as follows:
Specific aim 1) Demonstrate that unmethylated immunostimulatory CpG-containing DNA sequences (CpG DNA) induce signaling events culminating in NF-kappaB activation by bronchiolar epithelial cells.
Specific aim 2) Demonstrate that signaling events involving NF-kappaB activation modulate the inducible expression of the polymeric immunoglobulin receptor (plgr) in bronchiolar epithelial cells exposed to CpG DNA.
Specific aim 3) Demonstrate that Toll Like Receptor 9 (TLR9) mediates the activation of NF-kappaB and mRNA expression of pIgR in bronchiolar epithelial cells by CpG DNA.
Specific aim 4) Demonstrate that intranasal CpG DNA administration augments secretary immunoglobulin levels in the airway through TLR9-mediated NF-kB activation by bronchiolar epithelial cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Career Transition Award (K22)
Project #
5K22ES011652-03
Application #
6895941
Study Section
Special Emphasis Panel (ZES1-LKB-E (KT))
Program Officer
Shreffler, Carol K
Project Start
2003-09-15
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2007-06-30
Support Year
3
Fiscal Year
2005
Total Cost
$108,000
Indirect Cost
Name
University of Vermont & St Agric College
Department
Pathology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Bevelander, Mieke; Mayette, Jana; Whittaker, Laurie A et al. (2007) Nitrogen dioxide promotes allergic sensitization to inhaled antigen. J Immunol 179:3680-8
Poynter, Matthew E; Cloots, Roy; van Woerkom, Tiest et al. (2004) NF-kappa B activation in airways modulates allergic inflammation but not hyperresponsiveness. J Immunol 173:7003-9