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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE021685-03
Application #
8584230
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Burgoon, Penny W
Project Start
2012-02-01
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
3
Fiscal Year
2014
Total Cost
$360,000
Indirect Cost
$135,000
Name
University of Pennsylvania
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Mastellos, D C; Ricklin, D; Hajishengallis, E et al. (2016) Complement therapeutics in inflammatory diseases: promising drug candidates for C3-targeted intervention. Mol Oral Microbiol 31:3-17
Subramanian, Pallavi; Mitroulis, Ioannis; Hajishengallis, George et al. (2016) Regulation of tissue infiltration by neutrophils: role of integrin α3β1 and other factors. Curr Opin Hematol 23:36-43

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