|Support type:||Scholarships in Brazil - Doctorate|
|Effective date (Start):||June 01, 2009|
|Effective date (End):||May 31, 2012|
|Field of knowledge:||Health Sciences - Dentistry - Periodontology|
|Principal researcher:||Gustavo Pompermaier Garlet|
|Grantee:||Carlos Eduardo Palanch Repeke|
|Home Institution:||Faculdade de Odontologia de Bauru (FOB). Universidade de São Paulo (USP). Bauru , SP, Brazil|
The osseous destruction caused by the exacerbated activation of the immune system has been standing out within osseous inflammatory diseases, such as periodontal diseases (PDs). Thus, the mechanisms involved in the differentiation and the activation of osteoclasts have become one of the main targets in the study of such pathologies. Recent studies demonstrate that, in order for osteoclastogenesis to occur, not only is necessary the linking of molecules RANK/RANKL, but also of co-stimulatory molecules such as DAP12, TREM-2 and SIRP²1, and FcR³, OSCAR and PIR-A, which induce the signaling way of calcineurin/calcium, leading to an increase in the amount of intracellular calcium, fundamental for the activation of the NFATc1, the main factor of transcription in the differentiation and activation of osteoclasts. However, the possible contribution of such molecules to the progression of periodontal disease (experimental and human) remains unknown, due to the lack of studies on this subject. Preliminary results of our laboratory demonstrate an increase in the expression of such factors in biopsies of chronic periodontitis when compared to healthy tissues. As shown for the system RANK/RANKL, cytokines of different types (pro and anti-inflammatory, Th1 and Th17) exert a fundamental role in the development of inflammatory bone loss through the direct modulation of the factors involved in osteoclastogenesis, what potentially includes osteoclast co-stimulatory molecules. However, the degree of influence that different cytokines have on the expression of co-stimulatory molecules remains unknown. In this project, we will evaluate the kinetic of osteoclast co-stimulatory molecules expression (DAP12, TREM-2 and SIRP²1, and FcR³, OSCAR and PIR It) along the progression of experimental PD and the influence of different types of cytokines (pro-inflammatory: TNF-±; anti-inflammatory: IL-10; Th1: IFN-³; e Th17: IL-17) in its expression. Previous studies demonstrate an increased expression of such cytokines in periodontal lesions of human beings, as well as in the experimental model of PD in mice used by our research group. We will initially analyze the kinetic of osteoclast co-stimulatory molecules expression at periodontal lesions originated from oral inoculation of the periodontopathogen A. actinomycetemcomitans in mice of the isogenic lineage C57Bl/6, and its correlation with the levels of alveolar bone resorption and with the expression of RANK, RANKL and the target cytokines TNF-±, IL-10, IFN-³ and IL-17. After that, we will determine the role of these cytokines in the modulation of the expression of the co-stimulatory molecules having used mice that present mutations that make them genetically deficient for such cytokines (TNF-p55KO, IFN-³KO, IL-10KO and IL-17KO). For that matter, the following parameters will be analyzed, the severity of the experimental periodontitis (through the quantification of the alveolar bone resorption and the inflammatory infiltrate), the analysis of the expression of the target cytokines previously cited and the factors involved in bone resorption (RANK, RANKL, OPG and CatepsinaK), by RealTimePCR. The joint analyses of such data, involving the expression of osteoclastogenic factors and co-stimulatory molecules of osteoclasts, analyzed by the point of view of the bone loss resultant from the disease, certainly will collaborate for a better understanding of the osteoimmunology of periodontal disease, which might serve as a basis for the development of new strategies of prevention and therapy of such disease.