Localized aggressive periodontitis (LAP) affects 70,000 US children, largely from underserved communities. If untreated social and psychological stigma resulting from tooth loss can occur. This study is designed to identify early markers of aggressive periodontitis (eMAPs). Risk markers that include Aggregatibacter actinomycetemcomitans (Aa), other microbes, and host response elements will be examined over time. Adolescents will be screened to select a balanced cohort of 250 Aa-positive and 250 Aa-negative periodontally healthy students who will be enrolled and followed for 2 years. The purpose of this study is to detect microbial and host biomarkers that precede clinical evidence of bone loss (BL) with the aim of developing a chair-side diagnostic system for rapid identification of susceptible subjects. Thus far, we have developed a test that permits immediate chair-side identification of subjects with Aa, and a test for chemokines related to BL. However, our data indicates that Aa alone is not sufficient for diagnosis, and macrophage inflammatory protein 1-alpha (MIP-1?) while novel and related to BL can be improved upon by finding markers that identify earlier events. Clinical measurements and sampling of buccal epithelial cells (BECs), saliva, plaque, and crevice fluid will be performed every 3 months. Stored samples will be analyzed prospectively to assess host and microbial biomarkers (salivary, crevicular and microbial elements) that predate BL (Aa and MIP-1?) and predict bone loss in a subject (AIM 1a) and at a site (AIM 1b), and then to retrospectively determine new biomarkers that predate BL when a subject (AIM 2a) and a site develops radiographic signs of BL (AIM 2b).
AIM 1 a assesses whether Aa on buccal cells in combination with salivary MIP-1?an osteoclast promoter, can serve as predictive diagnostic markers for individuals who will develop LAP.
AIM 1 b assesses levels of: 1) the proposed antagonists (a consortium of subgingival bacteria including Aa, S. parasanguinis and F. alocis), and 2) host response element (crevicular MIP-1? as predictive markers of time-dependent risk for BL at a tooth sites within 6-9 months.
AIM 2 examines host and microbial markers that appear earlier than markers tested in AIM 1. After detection of BL, samples taken 3, 6, 9, and 12 months earlier will be tested for salivary and microbial factors that could promote colonization of the consortium on BECs at the subject level (AIM 2a). At the site level we will study the orchestration and timing of individual bacteria that make up the subgingival LAP consortium to determine if previously undetected bacteria (using NextGen sequencing) may also be involved in disease initiation. Further, sequential timing of early, middle, and late host cytokines as they appear in crevice fluid will be analyzed to identify biomarkers (AIM 2b) appearing at a BL site in advance of markers studied in AIM 1. Our premise is that the knowledge gained can provide sensitive and specific biomarkers that can supplant diagnostic tools used currently in practice. In this manner, subjects at risk can be identified in the earliest stages of disease so that cost-effective strategies can be instituted to reduce oral health disparities.

Public Health Relevance

We have developed a unique clinical model that permits us to examine and offer treatment to vulnerable underserved adolescent subjects as they progress from health to the early stages of localized aggressive periodontal disease. The current study design will provide us with the opportunity to evaluate subjects and sites within subjects every 3 months so that biomarkers discovered in our previous grant period can be used to predict bone loss in these subjects and sites that start out healthy and progress to disease. In addition, oral samples taken at 3-month intervals will now also be assessed after disease occurs to find new biomarkers that arise at earlier stages of disease by evaluating these biomarkers before disease was detected in order to translate these biomarkers into diagnostic tests to provide cost-effective preventive interventions that can reduce oral health disparities in underserved adolescent populations vulnerable to this aggressive form of periodontal disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE017968-07
Application #
9012801
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Gannot, Gallya
Project Start
2006-07-15
Project End
2020-01-31
Budget Start
2016-02-01
Budget End
2017-01-31
Support Year
7
Fiscal Year
2016
Total Cost
$633,973
Indirect Cost
$206,891
Name
Rbhs-School of Dental Medicine
Department
Dentistry
Type
Schools of Dentistry
DUNS #
078795856
City
Newark
State
NJ
Country
United States
Zip Code
07103
Cugini, Carla; Mei, Yongyi; Furgang, David et al. (2018) Utilization of Variant and Fusion Proteins To Functionally Map the Aggregatibacter actinomycetemcomitans Trimeric Autotransporter Protein ApiA. Infect Immun 86:
Velusamy, Senthil K; Sampathkumar, Vandana; Godboley, Dipti et al. (2017) Survival of an Aggregatibacter actinomycetemcomitans quorum sensing luxS mutant in the mouths of Rhesus monkeys: insights into ecological adaptation. Mol Oral Microbiol 32:432-442
Fine, D H (2015) Lactoferrin: A Roadmap to the Borderland between Caries and Periodontal Disease. J Dent Res 94:768-76
Fine, Daniel H; Markowitz, Kenneth; Fairlie, Karen et al. (2014) Macrophage inflammatory protein-1? shows predictive value as a risk marker for subjects and sites vulnerable to bone loss in a longitudinal model of aggressive periodontitis. PLoS One 9:e98541
Fine, Daniel H; Markowitz, Kenneth; Fairlie, Karen et al. (2013) A consortium of Aggregatibacter actinomycetemcomitans, Streptococcus parasanguinis, and Filifactor alocis is present in sites prior to bone loss in a longitudinal study of localized aggressive periodontitis. J Clin Microbiol 51:2850-61
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
Schreiner, Helen; Li, Yu; Cline, Joshua et al. (2013) A comparison of Aggregatibacter actinomycetemcomitans (Aa) virulence traits in a rat model for periodontal disease. PLoS One 8:e69382
Fine, Daniel H; Furgang, David; McKiernan, Marie et al. (2013) Can salivary activity predict periodontal breakdown in A. actinomycetemcomitans infected adolescents? Arch Oral Biol 58:611-20
Genderson, M W; Sischo, L; Markowitz, K et al. (2013) An overview of children's oral health-related quality of life assessment: from scale development to measuring outcomes. Caries Res 47 Suppl 1:13-21
Fine, Daniel H; Toruner, Gokce A; Velliyagounder, Kabilan et al. (2013) A lactotransferrin single nucleotide polymorphism demonstrates biological activity that can reduce susceptibility to caries. Infect Immun 81:1596-605

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