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Expression and regulation of inflammatory mediators associated with destruction of mineralized and non-mineralized tissues of the periodontium: study of the signaling pathways involved

Grant number: 06/04602-1
Support type:Scholarships abroad - Research
Effective date (Start): January 09, 2007
Effective date (End): March 08, 2007
Field of knowledge:Health Sciences - Dentistry
Principal Investigator:Carlos Rossa Junior
Grantee:Carlos Rossa Junior
Host: Luis Carlos Spolidorio
Home Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
Local de pesquisa : University of Michigan, United States  

Abstract

The immune-inflammatory response plays a fundamental role in periodontal disease, which is currently acknowledged as the result of an imbalance on a dynamic health-disease process, i.e., a consequence of changes on the interactions between microorganisms of the dental biofilm and the host response. This very concept implies on understanding periodontal diseases as infections that are both mediated and moduilated by the host response, since most of the tissue destruction results from the host’s inflammatory/immune response triggered by the presence of microorganisms as external aggressors. Thus, both the extent and severity of the disease are profoundly influenced by the immune/inflammatory response. This feature makes periodontal disease an interesting model for the study of other pathologies in which inflammation/immune response have a prominent role such as rheumatoid arthritis. As a health problem per se, periodontal diseases have considerable social and economic costs. In fact, its social costs might even be greater if the relationship between periodontal infection and general health issues is confirmed. The search for a better understanding of the immune response-mediated mechanisms involved in tissue destruction during periodontal diseases might yield relevant information that might useful not only to the treatment and prevention of periodontal diseases themselves but also for other pathologies. The purpose of this proposal is to study the expression and regulation of genes associated with inflammation and immune response during periodontal disease using both in vivo and in vitro models. Special emphasis will be given to the intracellular signaling pathways related with the control and regulation of gene expression. To this end, two experiments are proposed aiming to understand the molecular events associated with the expression of genes involved in soft and mineralized tissue destruction. Background information and rationale for the selection of MMP-13, RANKL and OPG as target genes is included in the introduction/justification of each experiment. One of the experiments proposed includes the modulation of immune response using FK506, which is an immunosuppressant increasingly being used for transplanted patients. The use of this drug not only allows the manipulation of the immunological system for the study of different aspects of the immune response, but it can also provide information that may give clues to a better understanding of the bone metabolism under the influence of this drug. The specific aims for the proposed experiments are:1)Experiment #1: Determine and localize the expression of MMP-13 in a ligature-induced model of periodontal disease, study the signaling pathways activated in this process and correlate this information with the activation of some transcription factors that are relevant for the expression of MMP-132)Experiment #2: Evaluate the expression of RANKL and OPG during ligature-induced periodontal disease in animals treated or not with FK-506 for inhibiting IL-2 signaling. Determine in vitro if specific inhibition of IL-2 has the same results of FK-506 and also to find out if the effects of FK-506 on gene expression are mediated by direct or indirect mechanisms. (AU)