Chaperones or heat shock proteins are found in all cells from bacteria to man and are among the most highly conserved and immunodominant molecules in nature. Originally thought to facilitate the three dimensional assembly of proteins it has become increasingly clear that these molecules have functions involving the immune response to a variety of microorganisms. In addition it has been shown that protective response to stress proteins may be involved in control of diseases like IBD, Legionella, Yersinia, Chlamydia and H. pylori infections and arteriosclerosis. The long-term goals of this work is to deliniate the mechanisms of chaperone involvement in periodontitis and periodontitis-related systemic disease and to develop strategies for medicinal treatment for those diseases. We have shown that elevated levels of antibodies to the HSP90 homolog (HtpG) of the periodontal pathogen P. gingivalis were found associated with better oral health in a group of gingivitis subjects. During our current grant we have demonstrated HtpG has the ability to induce immunomodulatory activity similar to chaperones from other bacteria associated with chronic infectious diseases. In periodontitis P. gingivalis HtpG recruits antibody producing cells to the lesion and upregulates chemokine receptors on both leukocytes and vascular cells contributing to the continuning tissue destruction. HtpG is found in circulation and CVD atheromas and can induce foam cell formation, an important step in atherosclerotic plaque formation. Antibodies to HtpG downregulate IL-8 production in both leukocytes and vein cells and may mitigate the inflammatory effects in periodontitis. This application will 1) chacterize the distinct receptor-mediated immunomodulatory activities of P. gingivalis HtpG in vitro;2) demonstrate the same activity in vivo in periodontitis and vascular tissue by microdisection, genomic/proteomic approaches;3) correlate serum antibodies to the presence of the molecules that drive this process. Such a demonstration will prepare the way for novel therapeutic and diagnostic modalities for both periodontitis and periodontitisrelated systemic diseases. PROJECT NARATIVE: Molecules that produce a particular class of proteins proteins in cells called chaperones can become involved in disease processes under some circumstances. Understanding the way this happens can lead to treatments for chronic diseases that are the result of long-lasting, unresolved periodontitis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE011117-10
Application #
7826763
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lunsford, Dwayne
Project Start
1996-04-01
Project End
2011-07-30
Budget Start
2010-05-01
Budget End
2011-07-30
Support Year
10
Fiscal Year
2010
Total Cost
$385,046
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biology
Type
Schools of Dentistry
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Sweier, Domenica G; Shelburne, P Sandra; Giannobile, William V et al. (2009) Immunoglobulin G (IgG) class, but Not IgA or IgM, antibodies to peptides of the Porphyromonas gingivalis chaperone HtpG predict health in subjects with periodontitis by a fluorescence enzyme-linked immunosorbent assay. Clin Vaccine Immunol 16:1766-73
Shelburne, Charles E; Shelburne, P Sandra; Dhople, Vishnu M et al. (2008) Serum antibodies to Porphyromonas gingivalis chaperone HtpG predict health in periodontitis susceptible patients. PLoS One 3:e1984
Shelburne, Charles E; Coopamah, Malini D; Sweier, Domenica G et al. (2007) HtpG, the Porphyromonas gingivalis HSP-90 homologue, induces the chemokine CXCL8 in human monocytic and microvascular vein endothelial cells. Cell Microbiol 9:1611-9
Shelburne, Charles E; An, Florence Y; Dholpe, Vishnu et al. (2007) The spectrum of antimicrobial activity of the bacteriocin subtilosin A. J Antimicrob Chemother 59:297-300
Kozarov, Emil; Sweier, Domenica; Shelburne, Charles et al. (2006) Detection of bacterial DNA in atheromatous plaques by quantitative PCR. Microbes Infect 8:687-93
Dhople, Vishnu; Krukemeyer, Amy; Ramamoorthy, Ayyalusamy (2006) The human beta-defensin-3, an antibacterial peptide with multiple biological functions. Biochim Biophys Acta 1758:1499-512
Ramamoorthy, Ayyalusamy; Thennarasu, Sathiah; Tan, Anmin et al. (2006) Deletion of all cysteines in tachyplesin I abolishes hemolytic activity and retains antimicrobial activity and lipopolysaccharide selective binding. Biochemistry 45:6529-40
Shelburne, Charles E; Coulter, Wilson A; Olguin, De'avlin et al. (2005) Induction of {beta}-defensin resistance in the oral anaerobe Porphyromonas gingivalis. Antimicrob Agents Chemother 49:183-7
Kozarov, Emil V; Dorn, Brian R; Shelburne, Charles E et al. (2005) Human atherosclerotic plaque contains viable invasive Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis. Arterioscler Thromb Vasc Biol 25:e17-8
Shelburne, C E; Gleason, R M; Coulter, W A et al. (2005) Differential display analysis of Porphyromonas gingivalis gene activation response to heat and oxidative stress. Oral Microbiol Immunol 20:233-8

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