REGULATION OF TGF-BETA SIGNALING BY EMILINS AND OTHER PROTEINS OF ELASTIC FIBER. ROLE IN MOUSE MODELS OF MONOGENIC FORMS OF HYPERTENSION, MARFAN SYNDROME AND SUPRA-VALVULAR AORTIC STENOSIS

Therapeutic management of a heritable diseases is not simply the consequence of the identification of the mutated gene. Instead, such therapy requires lot of information on how a mutated gene induces the alterations that constitute the distinguishing feature of the disease in order to identify existing drugs or to design new ones. In particular, it is very important to know which signaling pathways are influenced by the defective gene. A signaling pathway can be viewed as a series of biochemical reactions that regulate important functions of cells, such as proliferation, differentiation, movement and programmed death. This project wants to establish what signaling pathways are regulated by genes coding for molecules of the elastic fiber. Unpublished results and data in the literature have related such genes with the signaling pathway activated by a group of growth factors called TGF-beta. By defining how elastic fiber genes influence TGF-beta signaling at the molecular level, it will be possible to design drugs that re-establish the correct dynamic of the signaling pathway and prevent or attenuate the development of the associated disease. Heritable diseases related to components of elastic fiber are very important, as they include genetic forms of arterial hypertension, Marfan syndrome (one of the most frequent genetic diseases in human population) and supra-valvular aortic stenosis. In addition, the work is relevant for therapeutic applications in acquired diseases in which excessive TGF-beta signaling plays a major role. Such diseases include fibrosis of different organs, atherosclerosis and non-genetic forms of hypertension.