CHARACTERIZING THE MECHANISMS BY WHICH SEMAPHORINS CONTROL INTEGRIN FUNCTION DURING VASCULAR DEVELOPMENT

In human beings the first system to form is the cardiovascular system heart and blood vessels. This happens because, by transporting oxygen and nutrients, the cardiovascular system allows proper growth and function of all other tissues. Thus, malformations of the cardiovascular system could be lethal or cause hard problems to lead a normal life. Hereditary cardiovascular malformations are due to an altered capability of movement of cardiovascular cells. Cell motility relies upon adhesive interactions with the surrounding environment through cell surface molecules known as integrins, that act as hooks anchoring the cell to the extracellular matrix (ECM). The hook of integrins can be unlocked or locked, i.e. capable or incapable to interact with the ECM. During development a fine regulation of the integrin hooks control cell motility of cardiovascular cells and the correct formation of this important system. Therefore it is necessary to characterize the molecules that regulate locking and unlocking of integrin hooks. While much is known about the latter, little is known about the former. Recently, we have discovered that a class of molecules named semaphorins (SEMA) corrects the possible wrong movements of cardiovascular cells by locking their integrin hooks. Indeed, lack of SEMA causes errors in cardiovascular cell movements and hence in the formation of blood vessels. Now, we would like to understand the details of the molecular mechanism by which SEMA lock integrin hooks in cardiovascular cells minimizing their path errors. We will employ new biochemical and genetical techniques on cultured cells to identify these molecules. Then we will develop genetically modified animals devoid of these molecules that will allow us to verify their activity as SEMA messengers that regulate integrin function during cardiovascular development. In this way we will identify new pharmacological targets to cure hereditary cardiovascular malformations.