The investigator proposes to test the hypothesis that vascular expression of adhesion molecules and MCP-1 are key determinants of mononuclear cell recruitment to transplanted allografts. Further, he hypothesizes that recruited monocytes and T cells contribute to the development of neointimal thickening. To test these hypotheses the applicant proposes to use adenoviral vectors to over express adhesion molecules (ICAM-1, VCAM-1, E-selectin) with MCP-1 or an MCP-1 antagonist in in vitro and in vivo models.
In aim 1, they propose to develop the necessary vectors and define in vitro the role of these molecules in MCP-1 in mediating adhesion of specific leukocytes subsets to vascular endothelium under flow conditions.
In aim 2, they propose to optimize and characterize in vivo gene transfer in a rat aortic transplant model and in aim 3, they propose to express in transplanted aorta in vivo the molecules that effectively and specifically supported adhesion on mononuclear leukocytes. Finally, they will determine if expression of these molecules leads to recruitment of mononuclear leukocytes into the vessel wall and if recruitment of leukocytes induces neointimal formation.
