Assistant Member of the Staff
Department of Cytokine Biology
email:
Iwate Medical University, D.D.S., 1989, Dentistry
Iwate Medical University, Ph.D., 1998, Endodontics/Pathology/Histology
Periapical and marginal periodontitis are infections with pathogenic bacteria such as Fusobacterium nucleatum and Porphyromonas gingivalis that result in the loss of bony support of the teeth. The Sasaki laboratory explores the molecular mechanisms of host defense and bone loss in these dental diseases utilizing genetically engineered gene knockout and transgenic mice. We are also trying to translate our findings into practical applications.
We are exploring the functional role of the cytokines that mediate Th1 and Th2 type immune responses in periapical and marginal periodontitis. To date, we have reported that gene knockouts of Th2 type anti-inflammatory cytokines interleukin-10 (IL-10) and to a lesser extent IL-6, but not IL-4, resulted in enhanced infection-stimulated periapical and marginal bone loss. In contrast, the Th1 type cytokine IFNg, or its inducers IL-12 and IL-18, have no significant effects in these models, suggesting that pro-inflammatory pathways are highly redundant. Additional cytokines with the potential to regulate inflammation and immunity are being evaluated. The ultimate goal is to define the cytokine network that controls infection-stimulated bone resorption, and to identify potential points of therapeutic intervention. We recently demonstrated that IL-10 and IL-12 are key modulators in P. gingivalis-induced alveolar bone loss via suppressing/activating the Th1 pathway, and also indicate that IL-10 is functionally dominant over Th1-related cytokines in the cytokine network. Thus, the Th1 type cytokine IFNg, or its inducers IL-12 and IL-18, have no significant effects in these models as we previously reported. The goal is to define the cytokine network that controls infection-stimulated bone resorption, and to identify potential points of therapeutic intervention.
The role of innate immunity in mucosal inflammation
The role of Toll-like receptors (TLRs) signal on the cytokine network, which regulates mucosal inflammation including periodontitis and colitis, is being evaluated. In addition, we are investigating the role of osteopontin (OPN) in these diseases. The role of TLRs and OPN in IL-10 deficient mice is being assessed in vivo using double or triple mutant mice such as TLR4/IL-10 deficient mice.
Research and development of novel therapeutics for periapical and periodontal diseases
Our laboratory has established the IL-10 knockout mouse as novel animal models for periapical lesion and marginal periodontitis, in which bone loss is absolutely dependent upon infection with specific pathogens. The animal models will be utilized in the research and development of novel therapeutics for these diseases. The ultimate goal of this project is to provide novel therapeutics, which are highly safe, more effective, with less adverse effects and less costly, for the people suffering from oral inflammation.
Rittling SR, Zetterberg C, Yagiz K, Skinner S, Suzuki N, Fujimura A, Sasaki H. (2010) Protective role of osteopontin in endodontic infection. Immunology 129(1):105-114.
AlShwaimi E, Purcell P, Kawai T, Sasaki H, Oukka M, Campos-Neto A, Stashenko P. (2009) Regulatory T cells in mouse periapical lesions. J. Endod. 35(9):1229-1233.
Battaglino RA, PhamL, Morse LR, Vokes M, SharmaA, Odgren PR, Yang M, Sasaki H,Stashenko P. (2008) NHA-oc/NHA2: A mitochondrial cation-proton antiporter selectively expressed in osteoclasts. Bone 42(1):180-192.
Leshem O, Kashino SS, Goncalves RB, Suzuki N, Onodera M, Fujimura A, Sasaki H, Stashenko P, Campos-Neto A. (2008) Th1 biased response to novel Porphyromonas gingivalis protein aggravates bone resorption caused by this oral pathogen. Microbes Infect. 10(6):664-672.
Sasaki H, Suzuki N, Kent R Jr, Kawashima N, Takeda J, Stashenko P. (2008) T Cell response mediated by myeloid cell-derived IL-12 is responsible for Porphyromonas gingivalis-induced periodontitis in IL-10-deficient mice. J. Immunol. 180(9):6193-6198.
Kawai T, Paster BJ, Komatsuzawa H, Ernst CW, Goncalves RB, Sasaki H, Ouhara K, Stashenko PP, Sugai M, Taubman MA. (2007) Cross-reactive adaptive immune response to oral commensal bacteria results in an induction of receptor activator of nuclear factor-kappaB ligand (RANKL)-dependent periodontal bone resorption in a mouse model. Oral Microbiol. Immunol. 22(3):208-215.
Stashenko P, Goncalves RB, Lipkin B, Ficarelli A, Sasaki H, Campos-Neto A. (2007) Th1 immune response promotes severe bone resorption caused by Porphyromonas gingivalis. Am. J .Pathol. 170(1):203-213.
Visiting Scientists
Carla Sipert, D.D.S.
Research Assistant
Shuang Xu, M.S.
