Aggregatibacter actinomycetemcomitans (Aa) has been implicated as the causative agent of localized aggressive periodontitis (LAP), a severe form of periodontal disease that can lead to premature tooth loss in adolescents. This rapid form of periodontal disease affects more than 70,000 adolescents annually in the US alone. African-Americans have a 15-fold greater incidence of the disease than Caucasian-Americans making LAP a disproportionate burden on minorities and the poor. We recently have identified two new polymorphisms of the lactoferrin (Lf) gene that are involved in LAP. One polymorphic alteration occurs at the codon 11 (alanine/threonine) and the other is localized in the LPS binding region at codon 29 (arginine/lysine). Preliminary data suggests that genetic polymorphisms of Lf may play a significant role in determining an individual's susceptibility to the LAP. The research outlined in this revised proposal will test this hypothesis using a mouse model and focusing on the functional characterization of genetic polymorphisms of Lf.
The specific aims of the research are to 1) Generate bigenic Lf-variants/Lf-knockout mice;2) Determine the anti-bacterial and anti-inflammatory activities against Aa colonization and infection in bigenic Lf-variants/Lf-/- and Lf-/- mice. The results of the proposed research will contribute to our understanding of the functional role of Lf polymorphisms in LAP and provide new approaches to prevention of this disease based on functional differences in single nucleotide polymorphisms (SNPs) in the Lf gene.

Public Health Relevance

Aggregatibacter actinomycetemcomitans (Aa) has been implicated as the causative agent of localized Aggressive Periodontitis (LAP), a severe form of periodontal disease that can lead to premature tooth loss in adolescents. This rapid form of periodontal disease affects more than 70,000 adolescents in the US annually. African-Americans have a 15-fold greater incidence of disease than Caucasian Americans making LAP a disproportionate burden on minorities and the poor. Recently, we have identified two novel forms of genetic polymorphism of human lactoferrin. The alteration occurs at the codon 11 (Alanine (A)/Threonine (T) and other polymorphic alteration is localized in the LPS binding region of the Lf gene at the codon 29 (Argenine (R)/Lysine (K). Our preliminary results show that the A at position 11 and K at position 29 were predominantly found in LAP patients as opposed to T and R variants, respectively. The present proposal will test our hypothesis by focusing on the functional characterization of genetic polymorphism of Lf using a mouse model.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DE019548-02
Application #
8103861
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lunsford, Dwayne
Project Start
2010-08-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2011
Total Cost
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
781265475
City
Newark
State
NJ
Country
United States
Zip Code
07101
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Velliyagounder, K; Alsaedi, W; Alabdulmohsen, W et al. (2015) Oral lactoferrin protects against experimental candidiasis in mice. J Appl Microbiol 118:212-21
Velusamy, S K; Poojary, R; Ardeshna, R et al. (2014) Protective effects of human lactoferrin during Aggregatibacter actinomycetemcomitans-induced bacteremia in lactoferrin-deficient mice. Antimicrob Agents Chemother 58:397-404
Velusamy, Senthil Kumar; Fine, Daniel H; Velliyagounder, Kabilan (2014) Prophylactic effect of human lactoferrin against Streptococcus mutans bacteremia in lactoferrin knockout mice. Microbes Infect 16:762-7
Velusamy, S K; Ganeshnarayan, K; Markowitz, K et al. (2013) Lactoferrin knockout mice demonstrates greater susceptibility to Aggregatibacter actinomycetemcomitans-induced periodontal disease. J Periodontol 84:1690-701