Characterization of new pharmacological targets and study of the activity of a 4-phenyl coumarin in the differentiation of Th17 lymphocytes in the development of periodontal disease

Abstract

T helper lymphocytes 17 (Th17) play a key role in the development of periodontal disease due to its pro-inflammatory effects, becoming a promising target for the discovery of new drugs for the treatment of this disease. In the present study we aim to characterize new pharmacological targets and study the activity of cinnamoyloxy-mammeisin (CNM, a 4-phenyl coumarin) on the differentiation of Th17 lymphocytes in the development of periodontal disease. The present study is divided into 5 steps: 1) Characterization of the participation of Th17 lymphocytes (analysis of the frequency of IL17A and quantification of IL-17 and IL-22) and its main signaling pathways (Stat3, pStat3, Jak2, pJak2 , Socs3 and SHP1 by western blotting and gene expression of Rora, Rorc, IL17a, IL21, IL22 and IL23r) in the mice model of periodontitis induced by Porphyromonas gingivalis; 2) Conducting pharmacogenomic and bioinformatics tests for the characterization of new pharmacological targets that may be involved in the differentiation of Th17 lymphocytes during the development of experimental periodontal disease; 3) In vitro evaluation of CNM activity and mechanisms of action in naive T lymphocytes isolated from mice and differentiated for Th17; 4) In vivo activity of CNM in the differentiation of Th17 lymphocytes and in the development of periodontal disease induced by P. gingivalis in mice; And finally in the last step, 5) it will be tested the activity of CNM on differentiation of Th17 lymphocytes in human cells. This study seeks to characterize the participation of the main signaling pathways (kinases and phosphatases) involved in the differentiation of Th17 lymphocytes in the model of experimental periodontal disease. Also, to find new pharmacological targets involved in this event and propose a new naturally occurring drug which shows inhibitory activity in the development of periodontal disease by modulating the differentiation of Th17 lymphocytes. (AU)