Through the predecessor to this application (R01DE019456) we have been evaluating an underserved population of African-Americans in two health departments in North-Florida, diagnosed with an uncommon, aggressive form of periodontal disease known as localized aggressive periodontitis (LAP). Despite its low prevalence, we have compiled data from a cohort of over 100 LAP subjects, amongst a population which lacks specialized dental care for this disease. Specifically, we have discovered a TLR-induced hyper-inflammatory response in these subjects, which correlates with disease presentation and systemic levels of endotoxin. Importantly, this hyper-responsiveness is also observed in some periodontally healthy siblings of LAP subjects, indicating a potential genetically acquired and/or regulated predisposition for disease in these individuals. Therefore, the goal of this proposal is to expand on our discoveries and investigate inherited genetic contributions to regulation of inflammatory signaling involved in, and epigenetic regulation of thi TLR-induced hyper-inflammatory response under the condition of LAP. Importantly, association of these factors with treatment response and long-term stability will also be determined. Specifically, we will be expanding our clinical centers to recruit new subjects to reach a total of 200 LAP cases, 200 age-matched healthy siblings of LAP subjects and 200 unrelated healthy controls, African- Americans, aged 5-25 years old, and systemically healthy. We will and perform clinical examination and collect peripheral blood from all subjects to specifically reach these 3 aims: 1- Evaluate specific toll-like receptor (TLR) and cytokine Single Nucleotide Polymorphisms (SNPs) associated with hyper-inflammatory profile in LAP;2- Delineate the signaling events associated with TLR-induced hyper-responsiveness in LAP;and 3- Examine the role of diverse epigenetic modifications in the regulation of TLR-induced hyper-responsiveness in LAP. Importantly, the effect of periodontal therapy on the observed phenomenon will also be evaluated. Evaluation of these mechanisms will not only lead to improved outcomes of periodontal therapy, but are imperative for the prevention of the cyclical nature of disease recurrence observed in LAP, as well as disease initiation in healthy susceptible individuals. Furthermore, understanding the mechanisms behind this aggressive inflammatory response has enormous implications in the future health of these children, as hyper- inflammation is also involved in other, systemic, diseases such as diabetes and cardiovascular disease. Importantly, results from this proposal will hopefully lead to novel diagnostic and therapeutic targets for the prevention and successful long-term management of LAP.
We have discovered a TLR-induced hyper-inflammatory response in subjects with localized aggressive periodontitis, which is also observed in some periodontally healthy siblings of LAP subjects, indicating a potential genetically acquired and/or regulated predisposition for disease in these individuals. Therefore, the goal of this proposal is to expand on our discoveries and investigate inherited genetic contributions to regulation of inflammatory signaling involved in, and epigenetic regulation of this TLR-induced hyper- inflammatory response under the condition of LAP.
|Miller, Karina; Treloar, Tina; Guelmann, Marcio et al. (2018) Clinical Characteristics of Localized Aggressive Periodontitis in Primary Dentition. J Clin Pediatr Dent 42:95-102|
|Gonçalves, P F; Harris, T H; Elmariah, T et al. (2018) Genetic polymorphisms and periodontal disease in populations of African descent: A review. J Periodontal Res 53:164-173|
|Velsko, I M; Cruz-Almeida, Y; Huang, H et al. (2017) Cytokine response patterns to complex biofilms by mononuclear cells discriminate patient disease status and biofilm dysbiosis. J Oral Microbiol 9:1330645|
|Shaddox, L M; Mullersman, A F; Huang, H et al. (2017) Epigenetic regulation of inflammation in localized aggressive periodontitis. Clin Epigenetics 9:94|
|Branco-de-Almeida, L S; Cruz-Almeida, Y; Gonzalez-Marrero, Y et al. (2017) Local and Plasma Biomarker Profiles in Localized Aggressive Periodontitis. JDR Clin Trans Res 2:258-268|
|Miller, Karina A F S; Branco-de-Almeida, Luciana S; Wolf, Sandra et al. (2017) Long-term clinical response to treatment and maintenance of localized aggressive periodontitis: a cohort study. J Clin Periodontol 44:158-168|
|Burgess, Danielle K; Huang, Hong; Harrison, Peter et al. (2017) Non-Surgical Therapy Reduces Presence of JP2 Clone in Localized Aggressive Periodontitis. J Periodontol 88:1263-1270|
|Allin, N; Cruz-Almeida, Y; Velsko, I et al. (2016) Inflammatory Response Influences Treatment of Localized Aggressive Periodontitis. J Dent Res 95:635-41|
|Shaddox, Luciana M; Spencer, William P; Velsko, Irina M et al. (2016) Localized aggressive periodontitis immune response to healthy and diseased subgingival plaque. J Clin Periodontol 43:746-53|
|Kalash, D; Vovk, A; Huang, H et al. (2015) Influence of Periodontal Therapy on Systemic Lipopolysaccharides in Children with Localized Aggressive Periodontitis. Pediatr Dent 37:35-40|
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