Endothelial cell differentiation - a key to future therapy of chronic inflammation and cancer

Much attention is focused on understanding the role of vascular endothelial cells in disease. In several fields of medicine, there is great interest in understanding the mechanisms that regulate the generation of new vessels and endothelial cell different iation, because the future ability to manipulate these properties may enable future control of cancer growth and metastasis, drug targeting and leukocyte migration. We propose to characterize the molecular and cellular mechanisms of vascular morphogenesi s/angiogenesis in our surrogate in vivo model for human angio-genesis by global analysis of the endothelial cell transcription profiles during primitive tube formation and the recruitment of perivascular cells. In the course of these analyses we are also including samples from animals treated with the angiogenesis-inhibitor endostatin, which dramatically inhibits vascular morphogenesis in our model and shall use this data to validate other targets of inhibition. Furthermore, we shall pursue ongoing studie s focusing on understanding the molecular mechanisms of regulated secretion in endothelial cells, in one approach using chimeric, recombinant chemokines to decipher functionally important domains for their sorting to the Weibel Palade body, and in a secon d approach identifying the proteome of this compartment for regulated secretion. The proposed studies should expand our understanding of the critical role of endothelial cell differentiation in health and disease.