Novel Mechanisms and 'Complement-ary'Therapy in Periodontitis Project Summary Periodontal inflammation affects the majority of adults, while an estimated 10-15% develops severe periodontitis which exerts a systemic impact on the patients (e.g., increased risk for atherosclerosis and diabetes). However, the underlying immunopathology is poorly understood at the molecular level and effective, precisely targeted topical therapeutics are lacking. Clinical and histological observations, as well as experimental studies, suggest involvement of the complement system in periodontitis. However, the precise roles of the various complement pathways in periodontitis have not been defined. Consequently, it is currently uncertain which specific pathways or components need to be blocked to attenuate inflammatory pathology or, alternatively, maintained intact to support host defense. At a first stage, such mechanistic and interventional approaches necessitate the use of appropriate preclinical animal models. The overall objective of this proposal is to bridge the current mechanistic deficit of complement involvement in periodontitis to allow targeted intervention. The proposed project involves a consortium arrangement between the University of Louisville School of Dentistry and the University of Pennsylvania School of Medicine, and brings together leading, complementary, and integrated expertise in the areas of periodontal inflammation, microbial immune evasion, and complement-targeted therapeutics.
In Aim 1, a systematic approach is proposed to dissect the precise roles in periodontitis of individual pathways converging to or emanating from central complement hubs (C3, C5) that have already been implicated in preliminary studies.
In Aim 2, it is further proposed to investigate whether novel complement-dependent microbial evasion mechanisms, first identified by this group, promote both unwarranted inflammation and the cooperative survival of periodontal bacteria.
In Aim 3, those pathways or components that mediate destructive inflammation and/or pathogen persistence will be blocked, whereas those mediating host-protective effects will be kept intact. The experimental approach involves preclinical mouse models of inflammatory periodontitis and host-pathogen interactions. The mice to be used possess either intact complement system or carry specific mutations in key components that define major inductive or effector complement pathways. The translational approach involves the use of a panel of complement-specific therapeutic inhibitors. The availability of complement-specific drugs that have already undergone successful safety trials, indicates that promising interventions identified in this project have potential for rapid translation to clinical trials for periodontal disease treatment.
Novel Mechanisms and 'Complement-ary'Therapy in Periodontitis Project Narrative Conventional periodontal treatment is often not sufficient by itself to control destructive inflammation, which is mediated, in large part, through activities of the complement system. Our objective is to dissect mechanisms of complement involvement in periodontitis and accordingly apply appropriate complement-targeted drugs for treatment.
|Lamont, Richard J; Hajishengallis, George (2015) Polymicrobial synergy and dysbiosis in inflammatory disease. Trends Mol Med 21:172-83|
|Hajishengallis, George (2015) Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol 15:30-44|
|Mitroulis, Ioannis; Alexaki, Vasileia I; Kourtzelis, Ioannis et al. (2015) Leukocyte integrins: role in leukocyte recruitment and as therapeutic targets in inflammatory disease. Pharmacol Ther 147:123-35|
|Choi, E Y; Lim, J-H; Neuwirth, A et al. (2015) Developmental endothelial locus-1 is a homeostatic factor in the central nervous system limiting neuroinflammation and demyelination. Mol Psychiatry 20:880-8|
|Hajishengallis, George (2014) Aging and its Impact on Innate Immunity and Inflammation: Implications for Periodontitis. J Oral Biosci 56:30-37|
|Maekawa, Tomoki; Krauss, Jennifer L; Abe, Toshiharu et al. (2014) Porphyromonas gingivalis manipulates complement and TLR signaling to uncouple bacterial clearance from inflammation and promote dysbiosis. Cell Host Microbe 15:768-78|
|Huang, Yijun; Reis, Edimara S; Knerr, Patrick J et al. (2014) Conjugation to albumin-binding molecule tags as a strategy to improve both efficacy and pharmacokinetic properties of the complement inhibitor compstatin. ChemMedChem 9:2223-6|
|Hajishengallis, E; Hajishengallis, G (2014) Neutrophil homeostasis and periodontal health in children and adults. J Dent Res 93:231-7|
|Hajishengallis, G; Sahingur, S E (2014) Novel inflammatory pathways in periodontitis. Adv Dent Res 26:23-9|
|Maekawa, Tomoki; Abe, Toshiharu; Hajishengallis, Evlambia et al. (2014) Genetic and intervention studies implicating complement C3 as a major target for the treatment of periodontitis. J Immunol 192:6020-7|
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