Angiogenesis promotes the growth and spread of cancers, exacerbates the joint-impairing disease arthritis, and contributes to the blindness associated with diabetes and aging as well as the severity of the skin disease known as psoriasis. New approaches to stop the development of these new blood vessels are sought as potential therapies for these diseases. Thus there is a need for continued research into new treatments that can stop new blood vessel growth. Potential new targets in angiogenesis therapy are the integrin alpha5beta1 and its ligand fibronectin. Both molecules are required for the development of the embryonic vasculature. Murine knockouts of both of these proteins are embryonic lethal with severe defects in blood vessel formation. Recent studies from our laboratory indicate that integrin alpha5beta1 and fibronectin are minimally expressed on blood vessels in normal tissues. In contrast, their expression is significantly Hupregulated on vasculature in solid tumor cancers and in response to particular angiogenic growth factors. Furthermore, our studies in animal models of angiogenesis indicate that growth factor and tumor induced angiogenesis, as well as tumor growth, can be significantly inhibited by three classes of antagonists of integrin alpha5beta1 (antibodies, cyclic peptides and small organic molecules) and by antibody antagonists of fibronectin, the major ligand for alpha5beta1. The overall objective of this proposal is to evaluate in depth the roles of integrin alpha5beta1 and fibronectin in angiogenesis. We will test the hypothesis that fibronectin and its receptor integrin alpha5beta1 play critical roles in pathological tumor and inflammatory angiogenesis. Thus we plan to characterize the expression of integrin alpha5beta1 and fibronectin on the vasculature in normal and pathological tissues. We will evaluate the roles of integrin alpha5beta1 and fibronectin in angiogenesis induced by different growth factors, using the chick chorioallantoic membrane, the nude mouse xenotransplant and the SCID mouse/human skin chimera models of angiogenesis. Finally, we will analyze the role of integrin alpha5beta1 and fibronectin in tumor angiogenesis and growth. We will evaluate the efficacy of the three classes of integrin alpha5beta1 antagonists in the treatment of angiogenesis associated with solid tumor cancer in the chick chorioallantoic membrane, nude mouse and SCID mouse/human chimera tumor xenotransplant models as well as in the Mtag, p53 (-/-) and p53 (-/+) murine spontaneous tumor models. These studies may lead to the development of new approaches for the therapeutic modulation of angiogenic disease.
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