Molecular role and therapeutic potential of HA in endometriosis

CONICET has demonstrated that inhibition of HA synthesis using 4-methylumbelliferone (4-MU) at low doses, lead to a significant reduction of the vascularized area and functional microvessel density as revealed by in vivo imaging in a mouse model of endometriosis, which was supported by a diminished CD31 staining (Olivares et al, manuscript under revision). We will induce peritoneal endometriosis in BALB/c mice treated with 4-MU and evaluate its effect on endometriotic lesions regarding attachment, proliferation and apoptosis, as well as on angiogenesis and inflammation markers.We will study the role of CD44 and HA on endometriosis by performing the following experiments: 1- cell proliferation and apoptosis evaluation of endometrial stromal and epithelial cells obtained from endometriosis patients and controls treated with 4-MU in vitro; 2- validation of the results obtained on primary cell cultures on two endometrial epithelial and stromal cell lines treated with 4-MU in order to continue with objectives 3 and 4; 3- study of the pathways implicated in the results obtained on the endometrial cell lines treated with 4-MU in vitro, in particular the CD44, AKT/pAKT, ErbB2/pErbB2, beta-catenin and COX-2 pathway; 4- use siRNA approach at different levels of the pathway of interest evaluating how it affects cell survival; 5- evaluation of inflammation and angiogenesis related molecules modulation after treatment of primary cell cultures with 4-MU in vitro or after siRNA introduction in endometrial cell lines.