Free-living bacteria tend to associate with cell or inert surfaces to form surface-associated communities called biofilms. Gram-negative bacteria release small molecules called acyl homoserine lactones (AHLs) into the surrounding environment to communicate within and between species. When sufficient bacteria are present to form a """"""""quorum,"""""""" the AHLs reach high enough concentrations to trigger developmental programs that change the morphology and biochemical functionality of the cells to adapt them to life in a biofilm community. Among the changes incurred by this so-called quorum sensing system are loss of motility and gain of antibiotic resistance. Biofilms associated with chronic lung infections in cystic fibrosis and septic infections related to medical device implantation are difficult to eradicate with antibiotic therapy due to induction of resistance genes in the biofilm members. Persistent biofilms or bacterial overgrowths that are difficult to eradicate may produce large quantities of these AHLs. Recent evidence suggests that AHLs interact with eukaryotic cell signaling systems and can alter host gene expression. Preliminary molecular modeling suggests that AHLs may be able to bind to the human peroxisome proliferator-activated receptor gamma (PPARg), a nuclear receptor with important roles in inflammation, obesity, diabetes, and cardiovascular disease that binds a number of small molecule ligands. There is no data either in vitro or in vivo demonstrating whether AHLs in fact bind to eukaryotic nuclear receptors and alter gene transcription. We propose to determine whether bacterially derived AHLs can regulate eukaryotic gene transcription by activating host nuclear receptors including the PPARs, LXRs, FXR, CAR, PXR/SXR, ERs, TRs, and VDR. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Research Grants (R03)
Project #
5R03AI061526-02
Application #
6906415
Study Section
Special Emphasis Panel (ZRG1-IDM-N (90))
Program Officer
Korpela, Jukka K
Project Start
2004-07-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2007-06-30
Support Year
2
Fiscal Year
2005
Total Cost
$86,000
Indirect Cost
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010