PROJECT SUMMARY Fibrinogen is a multifunctional plasma protein that, after conversion into polymeric fibrin, promotes hemostasis and plays a pivotal role in various physiological and pathological processes, including wound healing, thrombosis, atherogenesis, tumorigenesis, and more. Inflammation and angiogenesis are integral parts of wound healing; however, in pathological settings, these two processes contribute to the development of inflammation-related cardiovascular diseases and the progression of tumor growth and metastasis. Our previous studies primarily focused on the newly discovered fibrin-VLDL receptor-dependent inflammatory pathway, which promotes the transendothelial migration of leukocytes and, consequently, inflammation. In these studies, we established the molecular mechanism underlying this pathway and hypothesized that the fibrin-derived β15-42 fragment, which was shown to exhibit significant protective effects in numerous inflammation-related animal models, inhibits this pathway by interacting with a putative receptor. Recently, we discovered that endothelial N-cadherin is a novel receptor for fibrin. Our extensive preliminary data suggest that N-cadherin is a putative receptor for β15-42, and the interaction of fibrin with this receptor promotes angiogenesis. Based on these data and our previous findings, we propose to characterize the novel fibrin-(N-cadherin) interaction and establish its role in fibrin-dependent inflammation and angiogenesis. Specifically, we aim to establish the structural basis for the fibrin-(N-cadherin) interaction (Specific Aim 1), test our hypothesis that N-cadherin is a putative receptor for the β15-42 fragment, whose interaction with this receptor inhibits leukocyte transmigration (Specific Aim 2), and test our hypothesis that fibrin-(N-cadherin) interaction triggers fibrin-dependent angiogenesis (Specific Aim 3). Additionally, we intend to design novel, efficient inhibitors of the fibrin-(N-cadherin) interaction with potent anti-inflammatory and anti-angiogenic properties. These inhibitors may be developed as potential therapeutics for treating fibrin-dependent inflammatory disorders and angiogenesis-related tumorigenesis.